The history of Mesa dates back at least 2,000 years to the arrival of the Hohokam people. The Hohokam, whose name means "All Used Up" or "The Departed Ones", built the original canal system. The canals were the largest and most sophisticated in the prehistoric New World. Some were up to 90 feet (27 m) wide and 10 feet (3.0 m) deep at their head gates, extending for as far as 16 miles (26 km) across the desert. By A.D. 1100 water could be delivered to an area over 110,000 acres (450 km²), transforming the Sonoran Desert into an agricultural oasis. By A.D. 1450, the Hohokam had constructed hundreds of miles of canals many of which are still in use today.

After the disappearance of the Hohokam and before the arrival of the early settlers little is known, as explorers did not venture into this area. By the late 19th century near present-day Mesa, U.S. Army troops relocated the Apache, opening the way for settlement.

Mormon pioneer Daniel Webster Jones, with Henry Clay Rogers as his right-hand man, left St. George, Utah in March 1877. Jones had been asked by Mormon officials to direct a party of people in establishing a settlement in Arizona. They traveled south and settled on the north side of the present Mesa area. This settlement was initially known as Fort Utah and later as Jonesville. It was located about where Lehi Road is now. In 1883 it was named Lehi at the suggestion of Brigham Young, Jr.

About this same time, another group dubbed the First Mesa Company arrived from Utah and Idaho. Their leaders were named Francis Martin Pomeroy, Charles Crismon, George Warren Sirrine and Charles I. Robson. Rather than accepting an invitation to settle at Jones' Lehi settlement, they moved up onto the mesa that serves as the city's namesake. They dug irrigation canals and used some of the original Hohokam canals. By April 1878, water was flowing through them. The Second Mesa Company arrived in 1879 and settled to the west of the First Mesa Company because of more available farmland. This settlement was called originally called Alma and later Stringtown. It was located about where Alma School Road is now.

On July 17, 1878, Mesa City was registered as a 1-square-mile (2.6 km²) townsite. The first school was built in 1879. In 1883, Mesa City was incorporated with a population of 300 people. Dr. A. J. Chandler, who would later go on to found the city of Chandler, worked on widening the Mesa Canal in 1895 to allow for enough flow to build a power plant. In 1917, the city of Mesa purchased this utility company. The revenues from the company provided enough for capital expenditures until the 1960s. During the Great Depression, WPA funds provided paved streets, a new hospital, a new town hall and a library.

After the founding of the city the elected official that most impacted the municipality was George Nicholas Goodman. He was mayor 5 different times</ref> in parts of 3 different decade (1938–1942, 1946–1948, 1952–1956) (see: List of mayors of Mesa, Arizona). As mayor he was directly involved in the process of acquiring land for both Falcon Field and Williams Field.

With the opening of Falcon Field and Williams Field in the early 1940s, more military personnel began to move into the Mesa area. With the advent of air conditioning and the rise of tourism, population growth exploded in Mesa as well as the rest of the Phoenix area. Industry—especially early aerospace companies—grew in the 1950s and 1960s. As late as 1960, half of the residents of Mesa made a living with agriculture, but this has declined substantially as Mesa's suburban growth continued on track with the rest of the Phoenix metro area.

According to the 2010 Census, the racial composition of Mesa was as follows:

As of the census of 2010, there were 439,041 people, 146,643 households, and 99,863 families residing in the city. The population density was 3,171.3 people per square mile (1,224.4/km²). There were 175,701 housing units at an average density of 1,405.7 per square mile (542.8/km²).

The racial make-up of the city was 81.6% White, 2.4% Black or African American, 2.2% Native American, 2.00% Asian, 0.10% Pacific Islander, 9.3% from other races, and 1.30% from two or more races. 24.0% of the population were Hispanic or Latino of any race.

There were 146,643 households, out of which 33.4% had children under the age of 18 living with them, 52.7% were married couples living together, 10.6% had a female householder with no husband present, and 31.9% were non-families. 24.2% of all households were made up of individuals, and 9.1% had someone living alone who was 65 years of age or older. The average household size was 2.68 and the average family size was 3.20.

The age distribution was 27.3% under 18, 11.2% from 18 to 24, 29.7% from 25 to 44, 18.4% from 45 to 64, and 13.3% who were 65 or older. The median age was 32 years. For every 100 females, there were 98.2 males. For every 100 females age 18 and over, there were 95.6 males.

The median income for a household in the city was $42,817, and the median income for a family was $49,232. Males had a median income of $35,960 versus $27,005 for females. The per capita income for the city was $19,601. About 6.2% of families and 8.9% of the population were below the poverty line, including 10.7% of those under age 18 and 7.1% of those age 65 or over.