The site of Mount Pleasant was originally occupied by the Sewee people, an Algonquian language-speaking tribe. The first European settlers arrived from England on July 6, 1680, under the leadership of Captain Florentia O'Sullivan. Captain O'Sullivan had been granted 2,340 acres (950 ha), which included not only the island later named for him, but also the future site of Mount Pleasant. On the earliest map of the time, this area was called "North Point".

In 1696, 51 new settlers arrived. Each family was allotted several hundred acres in the area that became known as Christ Church parish. In 1706 the Province of Carolina withstood several attacks by the Spanish and the French from their settlements to the south and were victorious in defeating French invaders in an area known as "Abcaw".

The area of "Abcaw" was Hobcaw Plantation, located between Shem Creek and the Wando River. Later, it was also known as Shipyard Plantation. Its access to deep water and abundance of good timber made it ideal for the development of a prosperous shipbuilding enterprise. Lands adjacent to Hobcaw Point were owned at different times by several different English families, many of which maintained ferries which served Mount Pleasant. By 1721, 107 families were living in Christ Church parish, including 400 whites and 637 enslaved Africans or African Americans. As the area was developed for large plantations, enslaved Africans and African Americans made up the chief labor force of the slave society. Based on this history, the majority of the population in the town was African American through the 19th and early 20th centuries.

In 1754, Charles Pinckney acquired a 715-acre plantation, cultivating the commodity crops of rice and indigo. It became known as Snee Farm near here. His son Charles retained the plantation until 1817. It was operated as a plantation through the 19th century.

On September 24, 1860, a public meeting was held in Mount Pleasant; it resulted in the first secession resolution passed in the state. The secession convention met in Charleston on December 20, 1860. With the advent of the Civil War, Battery Guerry and an adjacent floating battery between Mount Pleasant and Sullivan's Island were instrumental in defense of the city. They were also bases for attacks on Fort Sumter. The city was defended by a line of fortifications from Elliot's Creek at Boone Hall to Copahee Sound. Mount Pleasant was the secret training ground for the nine-man crew of the Confederate submarine H. L. Hunley, H.L. Hunley. This small vessel was launched from Breach Inlet in 1864 to attack and sink the USS Housatonic.

The original plank-and-barrel footbridge, later known as the Pitt Street Bridge at the foot of the Old Village area in Mount Pleasant, was used by the crew of the H.L. Hunley to cross to Breach Inlet to test the submarine. In 1899 the original wooden plank bridge was replaced by a trolley bridge.

A generation later, in 1929 a steel drawbridge was built for vehicle access between Sullivan's Island and Mount Pleasant. The Pitt Street bridge was dismantled in 1945, but the remains are visible in the Intracoastal Waterway. The area has been maintained since then as the Pickett Bridge Recreation Area. It was named for Charleston doctor Otis Pickett.

The "Old Village" is Mount Pleasant's oldest neighborhood; the oldest home, 111 Hibben Street (the Hibben House) was constructed in 1755 by Jacob Motte, a descendant of French Huguenots who had immigrated to South Carolina to escape religious persecution.

In the early 21st century, the Old Village is centered on the Pitt Street Shops at the northwestern end of the street. Among them is the Pitt Street Pharmacy, which was featured on the Food Network. It has operated at this location for more than 60 years.

The numerous slaves were freed during and after the Civil War. In 1875 African Americans made up 73% of the population in Charleston County. Whites used fraud and violence to suppress their voting and re-establish political dominance in the state, with Reconstruction ending in 1877.

Some of the freedmen developed Scanlonville, one of the first African-American communities to be formed after the Civil War in the Charleston area. Today it is a neighborhood within Mount Pleasant, having been annexed by the city. Robert Scanlon, a freedman carpenter, purchased the 614-acre (248 ha) property known as Remley's Plantation, bordering Charleston harbor along the Wando River in Mount Pleasant. Scanlon was the president and founder of the Charleston Land Company, formed by 100 local freedmen who pooled their limited resources and paid $10 per share, in order to purchase large tracts of land in the area. The Charleston Land Company divided this tract into smaller lots so that freedmen could have their own land. Remley's Plantation was divided into farm lots and city lots (which were smaller) to form the community of Scanlonville. The Charleston Land Company and Scanlonville are one of four known cooperative real estate development ventures among African-American freedmen after the Civil War.

West of Scanlonville is Riverside. During the Jim Crow years of much of the 20th century, this was known as the largest and oldest of five "black beaches" in Charleston County. It was established when public facilities were segregated under state law. Riverside officially opened in 1930 and featured a dance pavilion, athletics field, bathhouse, playground, and a boardwalk along the Wando River. Riverside Pavilion was the only venue where black city residents could see African-American musical legends such as Duke Ellington, Count Basie, Louis Armstrong, B.B. King, and Ivory Joe Hunter, who also performed in whites-only venues. Music performances at the Pavilion spawned juke joints, or night clubs, in Scanlonville and eventually a hotel called White's Paradise. James Brown was known to have frequented this hotel.

After the original park owner died in 1975, operations of the Riverside property were taken over by Charleston County. It eventually sold the property to a real estate company, which developed this area as a private gated community. Public access to the waterfront ended.

On September 21, 1989, Mount Pleasant was hit by Hurricane Hugo, a Category Four hurricane. While the town was spared from the worst of the storm (Category 4 conditions were suffered by areas further north of the city), the town and its neighboring barrier islands still had severe damage. Children who lived through the storm were featured in an early episode of Nickelodeon's Nick News, along with children who lived through Hurricane Andrew.

Development continued. A year after the storm, more people moved to the area, and the town had its largest growth spurt. It increased from a population of roughly 23,000 in 1990 to one of roughly 47,000 in 2000.

Mount Pleasant is separated from Charleston by the Cooper River. For many years, the town was populated largely on a seasonal basis by Charleston residents wealthy enough to afford summer homes across the river from the Charleston peninsula, where they would go believing they could escape the regular summer "fevers". The population of Mount Pleasant was centered in "Old Village".

The county seat for Berkeley County was located in Mount Pleasant from 1882 until 1895, when it was moved to Moncks Corner.

In 1928, a bridge from the Charleston Peninsula to Mount Pleasant was built. Spanning Town Creek and the Cooper River, and crossing the uninhabited Drum Island, the two-lane Grace Memorial Bridge was opened as a toll bridge. A second and larger bridge, the Silas N. Pearman Bridge, opened in 1966.

On July 16, 2005, the eight-lane Arthur Ravenel Bridge opened for automotive traffic, replacing the two aging bridges. It is one of the longest cable-stayed bridges in the Western Hemisphere. A week before the new bridge officially opened, pedestrians were allowed to cross the bridge, and commemorative coins were distributed. Also, a fireworks display was part of the ceremonies before the official opening. Several cars from the same time period as the Grace Memorial Bridge, including several restored Model A Fords, made a final crossing of the old bridges. The remaining portions of the old bridges were demolished. Local residents watched as the bridges were demolished by explosives over several weeks, through the summer of 2006.

In 2004, Mount Pleasant became one of the first municipalities in the United States to pass a "pay-before-you-pump" gas ordinance. It was intended to reduce stealing of gas that had accompanied rising prices.

The Auld Mound, Buzzard's Island Site, Christ Church, Cook's Old Field Cemetery, Long Point Plantation (38CH321), Lucas Family Cemetery, Mount Pleasant Historic District, Oakland Plantation House, Old Berkeley County Courthouse, Paul Pritchard Shipyard, Remley Point Cemetery, Slave Street, Smokehouse, and Allee, Boone Hall Plantation, Charles Pinckney National Historic Site, USS Clamagore (SS-343), USS Laffey (DD-724), and USS Yorktown (CV-10) are listed on the National Register of Historic Places.

As of the census of 2010, there were 67,843 people, 19,025 households, and 12,860 families residing in the city. The population density was 1,136.5 people per square mile (438.8/km²). There were 20,197 housing units at an average density of 482.1 per square mile (186.2/km²). The racial makeup of the city was 90.17% White, 7.25% African American, 0.17% Native American, 1.18% Asian, 0.02% Pacific Islander, 0.39% from other races, and 0.82% from two or more races. Hispanic or Latino of any race were 1.33% of the population.

There were 19,025 households, out of which 33.9% had children under the age of 18 living with them, 56.9% were married couples living together, 8.3% had a female householder with no husband present, and 32.4% were non-families. 24.1% of all households were made up of individuals, and 6.0% had someone living alone who was 65 years of age or older. The average household size was 2.47 and the average family size was 2.99.

In the town, the age distribution of the population shows 25.1% under the age of 18, 6.5% from 18 to 24, 35.3% from 25 to 44, 22.8% from 45 to 64, and 10.3% who were 65 years of age or older. The median age was 36 years. For every 100 females, there were 92.0 males. For every 100 adult females, there were 88.3 adult males.

The median income for a household in the town was $61,054, and the median income for a family was $71,165. Males had a median income of $50,673 versus $31,640 for females. The per capita income for the city was $30,823. About 3.2% of families and 5.0% of the population were below the poverty line, including 5.3% of those under age 18 and 6.6% of those age 65 or over.