The history of Mesa dates back at least two thousand 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 ten feet 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 subdued the Apache opening the way for settlement.

Daniel Webster Jones led an expedition to found a Mormon settlement in Arizona. Leaving St. George, Utah in March 1877, Jones and others arrived at Lehi, an area just north of present-day Mesa. Jones had been asked by LDS officials to direct a party of people in establishing a settlement in Arizona. This settlement was initially known as Jonesville and Fort Utah and did not receive the name of Lehi until 1883, when it was adopted on the suggestion of Brigham Young, Jr.

At the same time, another group dubbed the First Mesa Company arrived from Utah and Idaho. Their leaders were named Crismon, Pomeroy, Robson, and Sirrine. Rather than accepting an invitation to settle at Jones' Lehi settlement, they moved to the top of the mesa that serves as the city's namesake. They dug irrigation canals, some of which were over the original Hohokam canals, and by April 1878, water was flowing through them. The Second Mesa Company arrived in 1879 and settled to the east of where the First Mesa Company settled in 1880, due to lack of available farmland. This settlement was called Stringtown.

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 the 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.

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. The 1950s and 1960s showed growth of commerce and industry, especially from early aerospace companies. 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.

At the 2005-2007 American Community Survey Estimates, the city's population was 86.0% White (66.8% non-Hispanic White alone), 3.1% Black or African American, 2.5% American Indian and Alaska Native, 2.4% Asian, 0.2% Native Hawaiian and Other Pacific Islander, 8.1% from some other race and 2.2% from two or more races. 25.6% were Hispanic or Latino of any race.

As of the census 2001 estimate, there were 442,445 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/sq mi (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 population was diversified with respect to age with 27.3% under the age of 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 years of age 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. Mesa's residents exhibit a great deal of economic diversity, with low-income areas constructed somewhat close to high-scale neighborhoods with expensive custom homes. The neighborhood "Marlborough Mesa", along with many other neighborhoods, has won a community award.

Almost all of the city of Mesa is served by public schools operated by Mesa Public Schools; however, a small southern portion is served by the Gilbert Public Schools, and a small western portion is served by the Tempe Elementary School District and the Tempe Union High School District.

Mesa is also home to Mesa Community College, the largest of the Maricopa Community Colleges, which enrolls over 24,000 full and part time students. In addition, the Polytechnic campus of Arizona State University lies in southeast Mesa. This satellite campus enrolls over 6,000 undergraduate and graduate students in scientific and engineering fields.