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The Tucson area was probably first visited by Paleo-Indians, who were known to have been in southern Arizona about 12,000 years ago. Recent archaeological excavations near the Santa Cruz River found a village site dating from 2100 BC. The floodplain of the Santa Cruz River was extensively farmed during the Early Agricultural Period, circa 1200 BC to AD 150. These people constructed irrigation canals and grew corn, beans, and other crops, while also gathering wild plants and nuts, and hunting.

The Early Ceramic period occupation of Tucson saw the first extensive use of pottery vessels for cooking and storage. The groups designated as the Hohokam lived in the area from AD 600 to 1450 and are known for their vast irrigation canal systems and their red-on-brown pottery.

The Spanish Jesuit missionary Eusebio Francisco Kino first visited the Santa Cruz River valley in 1692. He founded the Mission San Xavier del Bac in 1700, about 7 mi (11 km) upstream from the site of the settlement of Tucson. A separate Convento settlement was founded downstream along the Santa Cruz River, near the base of what is now known as "A" mountain. Hugo O'Conor, the founding father of the city of Tucson, Arizona, authorized the construction of a military fort in that location, Presidio San Agustín del Tucsón, on August 20, 1775 (the present downtown Pima County Courthouse was built near this site). During the Spanish period of the presidio, attacks such as the Second Battle of Tucson were repeatedly mounted by the Apache. Eventually the town came to be called Tucsón, a Spanish version of the O'odham word for the area. It was included in the state of Sonora after Mexico gained independence from the Kingdom of Spain and its Spanish Empire in 1821.^{[citation needed]}

During the Mexican–American War in 1846–1848, Tucsón was captured by Philip St. George Cooke with the Mormon Battalion, but it soon returned to Mexican control as Cooke proceeded to the west, establishing Cooke's Wagon Road to California. Tucsón was not included in the Mexican Cession to the United States following the war. Cooke's road through Tucsón became one of the important routes into California during the California Gold Rush of 1849.^{[citation needed]}

The US acquired Arizona, south of the Gila River, via treaty from Mexico in the Gadsden Purchase on June 8, 1854. Under this treaty and purchase, Tucsón became a part of the United States of America. The American military did not formally take over control until March 1856. In time, the name of the town became standardized in English in its current form, where the stress is on the first syllable, the "u" is long, and the "c" is silent.

In 1857, Tucson was established as a stage station on the San Antonio-San Diego Mail Line. In 1858 it became 3rd division headquarters of the Butterfield Overland Mail and operated until the line was shut down in March 1861. The Overland Mail Corporation attempted to continue running; however, following the Bascom Affair, devastating Apache attacks on the stations and coaches ended operations in August 1861.^{[citation needed]}

Tucson was incorporated in 1877, making it the oldest incorporated city in Arizona.^{[citation needed]}

From 1877 to 1878, the area suffered a rash of stagecoach robberies. Most notable were the two holdups committed by masked road-agent William Whitney Brazelton. Brazelton held up two stages in the summer of 1878 near Point of Mountain Station, approximately 17 mi (27 km) northwest of Tucson. John Clum, of Tombstone, Arizona fame, was one of the passengers. Pima County Sheriff Charles A. Shibell and his citizen posse killed Brazelton on August 19, 1878, in a mesquite bosque along the Santa Cruz River 3 miles (5 km) south of Tucson. Brazelton had been suspected of highway robbery in the Tucson area, the Prescott region, and the Silver City, New Mexico area. Because of the crimes and threats to his business, John J. Valentine, Sr. of Wells, Fargo & Co. had sent Bob Paul, a special agent and a future Pima County sheriff, to investigate. The US Army established Fort Lowell, then east of Tucson, to help protect settlers and travelers from Apache attacks.

In 1882, Morgan Earp was fatally shot, in what was later referred to in the press as "the Earp-Clanton Tragedy". Marietta Spence, wife of Pete Spence, one of the Cochise County Cowboys, testified at the coroner's inquest on Earp's killing and implicated Frank Stilwell in the murder. The coroner's jury concluded Pete Spence, Stilwell, Frederick Bode, and Florentino "Indian Charlie" Cruz were the prime suspects in the assassination of Morgan Earp.

Deputy U.S. Marshal Wyatt Earp gathered a few trusted friends and accompanied Virgil Earp and his family as they traveled to Benson to take a train to California. They found Stilwell apparently lying in wait for Virgil Earp at the Tucson station and killed him on the tracks. After killing Stilwell, Wyatt deputized others and conducted a vendetta, killing three more cowboys over the next few days before leaving the Territory.

Jim Leavy had built a reputation of having fought in at least 16 gunfights. On June 5, 1882, Leavy had an argument with faro dealer John Murphy in Tucson. The two agreed to have a duel on the Mexican border, but after hearing of Leavy's exploits as a gunfighter, Murphy decided to ambush Leavy instead. Together with two of his friends, Murphy ambushed Leavy as he was leaving the Palace Hotel, killing him. According to Wright, the three co-defendants in Leavy's murder later escaped from the Pima County Jail, but were later recaptured. Murphy and Gibson were found in Fenner, California living under assumed names and retried for the murder before being found not guilty. Moyer was captured in Denver and sentenced to life in Yuma Territorial Prison, but was pardoned in 1888.

As other settlers tried to overcome violent frontier society, in 1885 the territorial legislature founded the University of Arizona as a land-grant college on what was over-grazed ranch land between Tucson and Fort Lowell.

In 1890, Asians made up 4.2% of the city's population. They were predominately Chinese men who had been recruited as workers on the railroads.

By 1900, 7,531 people lived in Tucson. By 1910, the population increased to 13,913. At about this time, the U.S. Veterans Administration had begun construction of the present Veterans Hospital. The city's clean, dry air made it a destination for the many veterans who had been gassed in World War I and needed respiratory therapy. In addition, these dry and high altitude conditions were thought to be ideal for the treatment of tuberculosis, for which there were no known cures before antibiotics were developed against it.

The city continued to grow, with the population increasing to 20,292 in 1920 and 36,818 in 1940. In 2006, the population of Pima County, in which Tucson is located, passed one million, while the City of Tucson's population was 535,000.^{[citation needed]}

In 1912, Arizona was admitted as a state. This increased the number of flags that had been flown over Tucson to five: Spanish, Mexican, United States, Confederate, and the State of Arizona.

During the territorial and early statehood periods, Tucson was Arizona's largest city and commercial center, while Phoenix was the seat of state government (beginning in 1889) and agriculture. The development of Tucson Municipal Airport increased the city's prominence. But between 1910 and 1920, Phoenix surpassed Tucson in population, and has continued to outpace Tucson in growth. In recent years, both Tucson and Phoenix have had some of the highest growth rates of any jurisdiction in the United States.

According to the 2010 American Census Bureau, the racial composition of Tucson was as follows:

As of the census of 2010, there were 520,116 people, 229,762 households, and 112,455 families residing in the city. The population density was 2,500.1 inhabitants per square mile (965.3/km²). There were 209,609 housing units at an average density of 1,076.7 per square mile (415.7/km²). The racial makeup of the city was 69.7% White (down from 94.8% in 1970), 5.0% Black or African-American, 2.7% Native American, 2.9% Asian, 0.2% Pacific Islander, 16.9% from other races, and 3.8% from two or more races. Hispanic or Latino of any race were 41.6% of the population.Non-Hispanic Whites were 47.2% of the population in 2010, down from 72.8% in 1970.

According to research by demographer William H. Frey using data from the 2010 United States Census, Tucson has the lowest level of black-white segregation of any of the 100 largest metropolitan areas in the United States.

There were 192,891 households, out of which 29.0% had children under the age of 18 living with them, 39.7% were married couples living together, 13.8% had a female householder with no husband present, and 41.7% were non-families. 32.3% of all households were made up of individuals, and 9.3% had someone living alone who was 65 years of age or older. The average household size was 2.42 and the average family size was 3.12.

In the inner-city, the population has 24.6% under the age of 18, 13.8% from 18 to 24, 30.5% from 25 to 44, 19.2% from 45 to 64, and 11.9% who were 65 years of age or older. The median age was 32 years. For every 100 females, there were 96.0 males. For every 100 females age 18 and over, there were 93.3 males.

The median income for a household in the city was $30,981, and the median income for a family was $37,344. Males had a median income of $28,548 versus $23,086 for females. The per capita income for the city was $16,322. About 13.7% of families and 18.4% of the population were below the poverty line, including 23.6% of those under age 18 and 11.0% of those age 65 or over.