Gainesville was established as "Mule Camp Springs" by European-American settlers in the early 1800s. Less than three years after the organization of Hall County on December 15, 1818, Mule Camp Springs was renamed "Gainesville" on April 21, 1821. It was named in honor of General Edmund P. Gaines, a hero of the War of 1812 and a noted military surveyor and road-builder. Gainesville was selected to be the county seat and chartered by the Georgia General Assembly on November 30, 1821.

A gold rush that began in nearby Lumpkin County in the 1830s resulted in an increase in the number of settlers and the beginning of a business community. In the middle of the 19th century, Gainesville had two important events. In 1849, it became established as a resort center, with people attracted to the springs. In 1851, much of the small city was destroyed by fire.

Around 1870, after the Civil War, Gainesville began to grow. In 1871 The Atlanta and Richmond Air-Line Railway, later re-organized into The Atlanta and Charlotte Air Line Railroad, began to stop in Gainesville, increasing its ties to other markets and stimulating business and population. It grew from 1,000 in 1870, to over 5,000 by 1900.

By 1898, textile mills had become the primary driver of the economy, with the railroad integral to delivering raw cotton and carrying away the mills' products. With the revenues generated by the mills, in 1902, Gainesville became the first city south of Baltimore to install street lamps. On March 1, 1905, free mail delivery began in Gainesville, and on August 10, 1910, the Gainesville post office was opened. On December 22, 1915, the city's first high-rise, the Jackson Building, had its formal opening. In 1919 Southern Bell made improvements to the phone system.

City services began in Gainesville on February 22, 1873, with the election of a City Marshal, followed by solid waste collection in 1874. In 1890, a bond issue to fund the waterworks was passed, and the original water distribution system was developed.

In 1943, at the height of World War II, Gainesville contributed to the war effort by leasing the airport to the US government for $1.00. The military used it as a naval air station for training purposes. In 1947, the airport was returned to the city of Gainesville, improved by the addition of two 4,000-foot (1,200 m) landing strips (one of which was later lengthened to 5,500 feet (1,700 m)).

After World War II, a businessman named Jesse Jewell started the poultry industry in north Georgia. Chickens have since become the state's largest agricultural crop. This $1 billion a year industry has given Gainesville the title "Poultry Capital of the World".

In 1956, the U.S. Army Corps of Engineers constructed Lake Sidney Lanier, by building Buford Dam on the Chattahoochee River. During the 1996 Summer Olympics, Gainesville served as the venue for the rowing and kayaking medal competitions, which were staged on Lake Lanier.

Gainesville gained accreditation of its Parks and Recreation Department in 2001. This was the third department in the state to be accredited. The Lakeside water treatment plant opened in 2002. The city has sponsored new social activities, including the Spring Chicken Festival in 2003, the Art in the Square gathering in 2004, and "Dredgefest" in 2008.

2008 saw the reopening of the Fair Street Neighborhood Center, the reopening of the Linwood Water Reclamation Facility Grand, and the completion of the Longwood Park Fishing Pier.

On January 28, 2021, a poultry plant in Gainesville leaked liquid nitrogen killing 6 and hospitalizing 12.

Gainesville is located in central Hall County at 34°18′16″N 83°50′2″W / 34.30444°N 83.83389°W / 34.30444; -83.83389 (34.304490, -83.833897). It is bordered to the southwest by the city of Oakwood. Interstate 985/U.S. Route 23 passes through the southern part of the city, leading southwest 54 miles (87 km) to Atlanta and northeast 23 miles (37 km) to Baldwin and Cornelia. U.S. Route 129 runs through the east side of the city, leading north 24 miles (39 km) to Cleveland and southeast 21 miles (34 km) to Jefferson.

According to the United States Census Bureau, the city has a total area of 33.9 square miles (87.7 km), of which 31.9 square miles (82.7 km) are land and 1.9 square miles (5.0 km), or 5.75%, are water.

Nestled in the foothills of the Blue Ridge Mountains, parts of Gainesville lie along the shore of one of the nation's most popular inland water destinations, Lake Lanier. Named after Confederate veteran, Georgia author and musician Sidney Lanier, the lake was created in 1956 when the U.S. Army Corps of Engineers dammed the Chattahoochee River near Buford and flooded the river's valley. Although created primarily for hydroelectricity and flood control, it also serves as a reservoir providing water to the city of Atlanta and is a very popular recreational attraction for all of north Georgia.

Much of Gainesville is heavily wooded, with both deciduous and coniferous trees.

Much like the rest of northern Georgia, Gainesville has a humid subtropical climate (Köppen climate classification Cfa), with cool to mild winters and hot, humid summers.

While Gainesville does not sit in Tornado Alley, a region of the United States where severe weather is common, supercell thunderstorms can sweep through any time between March and November, being primarily concentrated in the spring. Tornado watches are frequent in the spring and summer, with a warning appearing at least biannually, occasionally with more than one per year.

Tornado activity in the Gainesville area is above Georgia state average and is 108% greater than the overall U.S. average. Gainesville was the site of a deadly F4 on June 1, 1903, which killed 98 people. Gainesville was the site of the fifth deadliest tornado in U.S. history in 1936, in which Gainesville was devastated and 203 people were killed. In April 1974, an F4 tornado 22.6 miles away from the Gainesville city center killed six people and injured thirty. In December 1973, an F3 tornado 2.1 miles away from the city center injured twenty-one people. Both storms caused between $500,000 and $5,000,000 in property damages. On March 20, 1998, an F3 tornado impacted the Gainesville metro area early in the morning, killing 12 people and injuring 171 others. Another F3 tornado later that day killed 2 other people and injured a further 27 people in the Stoneville area.

As of the 2020 United States census, there were 42,296 people, 13,314 households, and 8,796 families residing in the city.

As of the census of 2010, there were 33,804 people, 11,273 households, and 7,165 families residing in the city. The population density was 1,161.6 people per square mile (448.5 people/km). There were 12,967 housing units at an average density of 445.6 units per square mile (172.0 units/km). The racial makeup of the city was 54.2% White, 15.2% African American, 0.6% Native American, 3.2% Asian, 0.2% Pacific Islander, 23.4% from other races, and 3.2% from two or more races. Hispanic or Latino residents of any race were 41.6% of the population.

There were 11,273 households, out of which 30.3% had children under the age of 18 living with them, 39.3% were married couples living together, 18.2% had a female householder with no husband present, and 36.4% were non-families. 28.9% of all households were made up of individuals, and 3.64% had someone living alone who was 65 years of age or older. The average household size was 2.85 and the average family size was 3.55.

Age distribution was 33.9% under the age of 20, 9.5% from 20 to 24, 29.2% from 25 to 44, 16.7% from 45 to 64, and 10.5% who were 65 years of age or older. The median age was 29.5 years. For every 100 females, there were 91.6 males. For every 100 females age 20 and over, there were 84.4 males.

The median income for a household in the city was $38,119, and the median income for a family was $43,734. Males had a median income of $26,377 versus $20,531 for females. The per capita income for the city was $19,439. About 24.9% of families and 29.1% of the population were below the poverty line, including 40.7% of those under age 18 and 17.6% of those age 65 or over. In May 2013, the unemployment rate was 6.9%, less than the overall rate in Georgia of 8.3%, the US of 7.6%

Of the population aged 15 years and over, 31.0% have never been married; 50.0% are now married; 2.4% are separated; 7.7% are widowed; and 9.9% are divorced.

Three African Americans, Beulah Rucker, E. E. Butler, and Ulysses Byas were educational pioneers in Gainesville and Hall County. Rucker founded Timber Ridge Elementary School, the first school for Black children in Gainesville, in 1911. In 1951 she established a night high school for African-American veterans, which was the only High School for veterans in Georgia. E. E. Butler served as an educator for just one year before earning his Physician's license. In 1954, he became one of two who became the first Black men on the Gainesville City Schools Board of Education, a very unusual situation in the United States. When the schools were integrated in 1969, Byas, like most Black school principals was offered a demotion. Rather than take a job as an assistant principal at Gainesville High School, he moved to Tuskegee, Alabama, where he became the nation's first Black school superintendent.

E. E. Butler High School was a segregated school created in 1962 in response to court demands for equalization of resources for Black students. After the integration of public schools, it was closed in 1969.

The Gainesville City School District holds pre-school to grade twelve, and consists of five elementary schools, a middle school, and a high school. The district has 282 full-time teachers and over 4,438 students. Its lone high school, Gainesville High School boasts several notable alumni, including Deshaun Watson, Cleveland Browns quarterback, Cris Carpenter, former professional baseball player (St. Louis Cardinals, Florida Marlins, Texas Rangers, Milwaukee Brewers), Tasha Humphrey, professional basketball player, and Micah Owings, current professional baseball player (Arizona Diamondbacks, Cincinnati Reds, San Diego Padres). The mascot for Gainesville High School is the Red Elephant.

The Hall County School District holds pre-school to grade twelve, and consists of twenty-one elementary schools, six middle schools, and seven high schools. The district has 1,337 full-time teachers and over 21,730 students. The high schools in this district have produced a number of notable alumni including, Connor Shaw, starting quarterback for the University of South Carolina Gamecocks football team; Casey Cagle, Lt. Governor, State of Georgia; James Mills, Georgia State Representative; A.J. Styles, professional wrestler; Deshaun Watson, starting quarterback for the Houston Texans, Mike "MoonPie" Wilson, former NFL football player; Chester Willis, former NFL football player; Jody Davis, former catcher for Chicago Cubs and Atlanta Braves baseball teams; Billy Greer, bass guitarist for progressive rock band Kansas; Corey Hulsey, former NFL Oakland Raiders football player; Robin Spriggs, author and actor; and Martrez Milner, American football tight end.

Notable private schools in Gainesville include: Riverside Military Academy, a private, college preparatory, boarding and day school for boys in grades 6 through 12; and Lakeview Academy, a private, nondenominational, coeducational day school for students in preschool through 12th grade. From 1928 to 2011, Gainesville was also home to Brenau Academy, a female, college preparatory, residential school for grades 9–12, and a part of the Brenau University system. However, in 2011 Brenau Academy was revamped into a program allowing qualified young women to earn college credits during the time in their lives in which they would normally complete high school studies.

Gainesville has several institutions of higher education: University of North Georgia (formerly Gainesville State College), which was established January 8, 2013, as a result of the consolidation of North Georgia College and State University and Gainesville State College; Brenau University, a private, not-for-profit, undergraduate- and graduate-level higher education institution; the Interactive College of Technology; and Lanier Technical College.