The area now known as Tennessee was first settled by Paleo-Indians nearly 11,000 years ago. The names of the cultural groups that inhabited the area between first settlement and the time of European contact are unknown, but several distinct cultural phases have been named by archaeologists, including Archaic, Woodland, and Mississippian, whose chiefdoms were the cultural predecessors of the Muscogee people who inhabited the Tennessee River Valley prior to Cherokee migration into the river's headwaters.

When Spanish explorers first visited Tennessee, led by Hernando de Soto in 1539−43, it was inhabited by tribes of Muscogee and Yuchi people. Possibly because of European diseases devastating the native tribes, which would have left a population vacuum, and also from expanding European settlement in the north, the Cherokee moved south from the area now called Virginia. As European colonists spread into the area, the native populations were forcibly displaced to the south and west, including all Muscogee and Yuchi peoples, the Chickasaw, and Choctaw. From 1838 to 1839, nearly 17,000 Cherokees were forced to march from "emigration depots" in Eastern Tennessee, such as Fort Cass, to Indian Territory west of Arkansas. This came to be known as the Trail of Tears; as an estimated 4,000 Cherokees died along the way.

The area around Clarksville was first surveyed by Thomas Hutchins in 1768. He identified Red Paint Hill, a rock bluff at the confluence of the Cumberland and Red Rivers, as a navigational landmark.

In the years between 1771 and 1775, John Montgomery, the namesake of the county, along with Kasper Mansker, visited the area while on a hunting expedition. In 1771, James Robertson led a group of 12 or 13 families involved with the Regulator movement from near where present-day Raleigh, North Carolina now stands. In 1772, Robertson and the pioneers who had settled in northeast Tennessee (along the Watauga River, the Doe River, the Holston River, and the Nolichucky River) met at Sycamore Shoals to establish an independent regional government known as the Watauga Association. However, in 1772, surveyors placed the land officially within the domain of the Cherokee tribe, who required negotiation of a lease with the settlers. Tragedy struck as the lease was being celebrated, when a Cherokee warrior was murdered by a white man. Through diplomacy, Robertson made peace with the Cherokee, who threatened to expel the settlers by force if necessary.

In March 1775, land speculator and North Carolina judge Richard Henderson met with more than 1,200 Cherokees at Sycamore Shoals, including Cherokee leaders such as Attacullaculla, Oconostota, and Dragging Canoe. In the Treaty of Sycamore Shoals (also known as the Treaty of Watauga), Henderson purchased all the land lying between the Cumberland River, the Cumberland Mountains, and the Kentucky River, and situated south of the Ohio River in what is known as the Transylvania Purchase from the Cherokee Indians. The land thus delineated, 20 million acres (81,000 km²), encompassed an area half as large as the present state of Kentucky. Henderson's purchase was in violation of North Carolina and Virginia law, as well as the Royal Proclamation of 1763, which prohibited private purchase of American Indian land. Henderson may have mistakenly believed that a newer British legal opinion had made such land purchases legal.

All of present-day Tennessee was once recognized as Washington County, North Carolina. Created in 1777 from the western areas of Burke and Wilkes Counties, Washington County had as a precursor a Washington District of 1775–76, which was the first political entity named for the Commander-in-Chief of American forces in the Revolution.

In 1779, Hadley W. and Hannah W. brought a group of settlers from upper East Tennessee via Daniel Boone's Wilderness Road. Hadley and Hannah later built an iron plantation in Cumberland Furnace.^{[citation needed]} A year later, John Donelson led a group of flat boats up the Cumberland River bound for the French trading settlement, French Lick (or Big Lick), that would later be Nashville. When the boats reached Red Paint Hill, Moses Renfroe, Joseph Renfroe, and Solomon Turpin, along with their families, branched off onto the Red River. They traveled to the mouth of Parson's Creek, near Port Royal, and went ashore to settle down.^{[citation needed]} However, an attack by Indians in the summer drove them back. (See Port Royal State Park)

Clarksville was designated as a town to be settled in part by soldiers from the disbanded Continental Army that served under General George Washington during the American Revolutionary War.^{[citation needed]} At the end of the war, the federal government lacked sufficient funds to repay the soldiers, so the Legislature of North Carolina, in 1790, designated the lands to the west of the state line as federal lands that could be used in the land grant program. Since the area of Clarksville had been surveyed and sectioned into plots, it was identified as a territory deemed ready for settlement. The land was available to be settled by the families of eligible soldiers as repayment of service to their country.

The development and culture of Clarksville has had an ongoing interdependence between the citizens of Clarksville and the military. The formation of the city is associated with the end of the American Revolutionary War. During the Civil War a large percent of the male population was depleted due to Union Army victories at Fort Henry and Fort Donelson. Many Clarksville men were interned at Union prisoner of war (POW) camps. Clarksville also lost many native sons during World War I. With the formation of Camp Campbell, later Fort Campbell, during World War II, the bonds of military influence were strengthened. Soldiers from Fort Campbell, Kentucky have deployed in every military campaign since the formation of the post.^{[citation needed]}

On January 16, 1784, John Armstrong filed notice with the Legislature of North Carolina to create the town of Clarksville, named after General George Rogers Clark.^{[citation needed]} Even before it was officially designated a town, lots had been sold. In October 1785, Col. Robert Weakley laid off the town of Clarksville for Martin Armstrong and Col. Montgomery, and Weakley had the choice of lots for his services. He selected Lot #20 at the northeast corner of Spring and Main Streets. The town consisted of 20 'squares' of 140 lots and 44 out lots. The original Court House was on Lot #93, on the north side of Franklin Street between Front and Second Street. The Public Spring was on Lot #74, on the northeast corner of Spring and Commerce Streets. Weakley built the first cabin there in January 1786, and about February or March, Col. Montgomery came there and had a cabin built, which was the second house in Clarksville. After an official survey by James Sanders, Clarksville was founded by the North Carolina Legislature on December 29, 1785. It was the second town to be founded in the area. Armstrong's layout for the town consisted of 12 four-acre (16,000 m²) squares built on the hill overlooking the Cumberland as to protect against floods.^{[citation needed]} The primary streets (from north to south) that went east-west were named Jefferson, Washington (now College Street), Franklin, Main, and Commerce Streets. North-south streets (from the river eastward) were named Water (now Riverside Drive), Spring, First, Second, and Third Streets.

The tobacco trade in the area was growing larger every year and in 1789, Montgomery and Martin Armstrong persuaded lawmakers to designate Clarksville as an inspection point for tobacco.^{[citation needed]} In 1790, Isacc Rowe Peterson staked a claim to Dunbar Cave, just northeast of downtown.

When Tennessee was founded as a state on June 1, 1796, the area around Clarksville and to the east was named Tennessee County. (This county was established in 1788, by North Carolina.) Later, Tennessee County would be broken up into modern day Montgomery and Robertson counties, named to honor the men who first opened up the region for settlement.

Clarksville grew at a rapid pace. By 1806, the town realized the need for an educational institution, and it established the Rural Academy that year. It was later replaced by the Mount Pleasant Academy. By 1819, the newly established town had 22 stores, including a bakery and silversmith. In 1820, steamboats begin to navigate the Cumberland, bringing hardware, coffee, sugar, fabric, and glass.^{[citation needed]} The city exported flour, tobacco, cotton, and corn to ports such as New Orleans and Pittsburgh along the Ohio and Mississippi rivers.

Trade via land also grew as four main dirt roads were established, two to Nashville, one crossing the Red River via ferry called the Kentucky Road, and Russellville Road.^{[citation needed]} In 1829, the first bridge connecting Clarksville to New Providence was built over the Red River. Nine years later, the Clarksville-Hopkinsville Turnpike was built. Railroad service came to the town on October 1, 1859 in the form of the Memphis, Clarksville and Louisville Railroad. The line would later connect with other railroads at Paris, Tennessee, and Guthrie, Kentucky.

By the start of the Civil War, the combined population of the city and the county was 20,000. Planters in the area depended on slavery for the labor-intensive tobacco industry, one of the major commodity crops. In 1861, both Clarksville and Montgomery County voted unanimously for the state to secede and join the Confederate States of America. The birthplace of Confederate President Jefferson Davis was about 20 miles across the border in Fairview, Christian County, Kentucky. Both sides considered the city to be of strategic importance.

Confederate General Albert Sidney Johnston set up a defense line around Clarksville expecting a land attack. The city was home to three Confederate States Army camps:

The Union sent troops and gunboats down the Cumberland River, and in 1862 captured Fort Donelson, Fort Henry, and Clarksville. On February 17, 1862, the USS Cairo along with another Union Ironclad came to Clarksville and captured the city. There were no Confederate soldiers to contend with because they had left prior to the arrival of the ships. White flags flew over Ft. Defiance and over Ft. Clark. The citizens of the town who could get away, left as well. Before they left, Confederate soldiers tried to burn the railroad bridge that crossed the Cumberland River. The fire did not take hold and was put out before it could destroy the bridge. This railroad bridge made Clarksville very important to the Union. The USS Cairo tied up in Clarksville for a couple of days before moving on to participate in the capture of Nashville.

Between 1862 and 1865, the city would shift hands, but the Union retained control of Clarksville, including control of the city's newspaper, The Leaf Chronicle, for three years. Many slaves who had been freed or escaped gathered in Clarksville and joined the Union Army, which created all-black regiments. The 16th United States Colored Infantry regiment was mustered in at Clarksville.^{[citation needed]} Other freed slaves lived along the side of the river in shanties.

After the war, the city began Reconstruction, and in 1872, the existing railroad was purchased by the Louisville & Nashville Railroad. The city was flourishing until the Great Fire of 1878, which destroyed 15 acres (60,000 m²) of downtown Clarksville's business district, including the courthouse and many other historic buildings. It was believed to have started in a Franklin Street store. After the fire, the city rebuilt. The first automobile rolled into town, drawing much excitement.

In 1913, the Lillian Theater, Clarksville's first "movie house" for motion pictures, was opened on Franklin Street by Joseph Goldberg. It seated more than 500 people. Less than two years later, in 1915, the theater burned down. It was rebuilt later that year.^{[citation needed]}

As World War I raged in Europe, many locals volunteered to go, reaffirming Tennessee as the Volunteer State, a nickname earned during the War of 1812, the Mexican–American War and other earlier conflicts. Also during this time, women's suffrage was becoming a major issue. Clarksville women saw a need for banking independent of their husbands and fathers who were fighting. In response, the First Women's Bank of Tennessee was established in 1919 by Mrs. Frank J. Runyon.

The 1920s brought additional growth to the city. A bus line between Clarksville and Hopkinsville was established in 1922. In 1927 the Austin Peay Normal School was founded, later to develop as Austin Peay State University. In 1928 two more theaters were added, the Majestic (with 600 seats) and the Capitol (with 900 seats). John Outlaw, a local aviator, established Outlaw Field in 1929.

With the entry of the United States into World War II, defense investments were made in the area. In 1942 construction started on Camp Campbell (now known as Fort Campbell), the new army base ten miles (16 km) northwest of the city. It was capable of holding 23,000 troops, and as staffing built up, the base gave a huge boost to the population and economy of Clarksville.

In 1954, the Clarksville Memorial Hospital was founded along Madison Street. Downtown, the Lillian was renamed the Roxy Theater, and today it still hosts plays and performances weekly. The Roxy has been used as a backdrop for numerous photo shoots, films, documentaries, music videos and television commercials;^{[citation needed]} most notably for Sheryl Crow's Grammy-award-winning song "All I Wanna Do."^{[citation needed]}

Since 1980, the population of Clarksville has more than doubled, in part because of annexation, as the city acquired communities such as New Providence and Saint Bethlehem. The construction of Interstate 24 north of Saint Bethlehem added to its development potential and in the early 21st century, much of the growth along U.S. Highway 79 is commercial retail. Clarksville is currently one of the fastest-growing large cities in Tennessee. At its present rate of growth, the city was expected to displace Chattanooga by 2020 as the fourth-largest city in Tennessee.

On the morning of January 22, 1999, the downtown area of Clarksville was devastated by an F3 tornado, damaging many buildings including the county courthouse. The tornado, 880 yards (800 m) wide, continued on a 4.3-mile (6.9 km)-long path that took it north to Saint Bethlehem. No one was seriously injured or killed in the destruction. Clarksville has since recovered, and has rebuilt much of the damage. Where one building on Franklin Street once stood has been replaced with a large mural of the historic buildings of Clarksville on the side of one that remained.

On Sunday, May 2, 2010, Clarksville and a majority of central Tennessee, to include Nashville and 22 counties in total, suffered expansive and devastating floods near the levels of the great flood of 1937. Many businesses along Riverside Drive along the Cumberland River were lost.

On the evening of February 24, 2018, the east side of Clarksville was struck by a strong EF-2 tornado. Two injuries were reported and a spokesperson for the Montgomery County Sheriffs Office stated four homes and two duplexes were destroyed, dozens more damaged and 75 vehicles damaged at the nearby Hankook Tire plant. The tornado had maximum sustained winds of 125 mph (201 km/h), a path length of 4.05 mi (6.52 km), and a maximum width of 300 yd (270 m).

The first Montgomery County courthouse was built from logs in 1796 by James Adams. It was located close to the riverbank with the rest of the early town, on the corner of present-day Riverside Drive and Washington Street. It was replaced by a second courthouse built in 1805, and a third in 1806, with land provided by Henry Small. The fourth courthouse was built in 1811, and was the first to be built of brick. It was constructed on the east half of Public Square, with land donated by Martin Armstrong. In 1843, a courthouse was built at a new location on Franklin Street. It was destroyed in the Great Fire of 1878.

The sixth courthouse was built between Second and Third Streets, with the cornerstone laid on May 16, 1879. It was designed by George W. Bunting of Indianapolis, Indiana. Five years later, the downtown area was hit by a tornado, which damaged the roof of the courthouse. It was repaired. On March 12, 1900, the structure was ravaged by fire, with the upper floors gutted and the clock tower destroyed. Some citizens wanted the building replaced, but the judge refused and ordered the damage repaired.

The courthouse was destroyed by the January 22, 1999 tornado. Residents considered replacing it with a new building, but decided to restore and reconstruct the historic structure. In the process it was upgraded and adapted for use as a county office building. On the fourth anniversary of the disaster, the courthouse was rededicated. In addition to restoring the 1879 courthouse and plazas, the county built a new courts center on the north side for the court operations.

According to the U.S. Census Bureau, the 2017 population estimate for Clarksville was 153,205. Of that total, 66.6% were white, 23.1% were African-American, 10.8% were Hispanic or Latino, 4.9% multiple races, 2.4% Asian, 0.5% American Indian and Alaska Native, and 0.5% Native Hawaiian and other Pacific Islander.

The 2010 census estimated that 51.3% of the population in Clarksville were female, while 48.7% were male.

Of the 51,776 households, 38.8% had children under the age of 18 living with them, 48.9% were married couples living together, 17.3% had a female householder with no husband present, and 29.1% were not families. About 23.0% of all households were made up of individuals, and 5.1% had someone living alone who was 65 years of age or older. The average household size was 2.63 and the average family size was 3.09.

The median income for a household in the city was $48,679, and for a family was $56,295. Males had a median income of $41,019 versus $31,585 for females. The per capita income for the city was 23,722 (4th highest per capita personal income in Tennessee). About 12.4% of families and 16.5% of the population were below the poverty line, including 23.4% of those under age 18 and 11.5% of those age 65 or over.