His expedition met a large Native American group called the northern Utina, possibly near present-day Lake City, who were part of the western Timucua people.

In the 17th century Spanish missionaries established missions in this area, west of the site of present-day Lake City.

Called Santa Cruz de Tarihica, it was used by the Spanish to develop agriculture and bring Native Americans within their sphere.

[7] In the 18th century, a Seminole community called Alligator Village (Alapata Telophka) occupied this area.

By 1845, the last of the Seminole left the area of present-day Lake City or were forcibly removed by the US Army.

[9] In 1847, Company C of the Florida Volunteers, which was composed of Lake City members, served in the Mexican–American War.

In November 1858, a railroad was completed connecting Jacksonville to Alligator, which opened the town to more commerce and passenger traffic.

[11] During the American Civil War the railroad between Lake City and Jacksonville was used to send beef and salt to Confederate soldiers.

[13] Confederate General Joseph Finnegan assembled troops and called for reinforcements from P. G. T. Beauregard in response to the Union threat.

On February 11, 1864, Finnegan's troops defeated a Union cavalry raid in Lake City.

[13] After the Union cavalry was repulsed, Finnegan moved his forces to Olustee Station about ten miles east of Lake City.

The Confederate presence at Olustee Station was reinforced to prepare for the Union troops coming from Jacksonville.

[5] Florida Agricultural College was established in 1884 as part of the Morrill Land Grant Act; in 1904 it became a full university with twenty-five instructors.

NAS Lake City was a support facility for Naval Air Station Jacksonville and trained pilots to fly the Lockheed Ventura.

Military operations at NAS Lake City ended in March 1946, and it was decommissioned as an active naval air station.

[18] After World War II a local air base was converted for use in 1947 as the Columbia Forestry School.

The forestry products industry (turpentine, lumber, and pulpwood) had become a mainstay of the local economy.

Lake City's centennial was celebrated in 1959 with parades, fireworks, and a 58-page book documenting one hundred years of progress, A Century in the Sun.

[23] Lake City is part of the humid subtropical climate zone of the Southeastern United States.

Due to its latitude and relative position north of Florida's peninsula it is subject at times to continental conditions, which cause rare cold snaps that may affect sensitive winter crops.

Evangelicalism is the largest religious affiliation with 27.9% followed by Protestant (4.7%), Black Protestantism (3.5%), Catholicism (2.4%) and other religions (1.6%).

The basis of the ministry was that Lake City would be the only place to survive Armageddon and believers were to stay in an underground bunker on Meade's property.

Since 2000, three companies have begun large operations in Lake City: Hunter Panels, New Millennium and United States Cold Storage.

Target built their first company-owned and third-party-operated perishable food distribution center in Lake City in 2008.

The festival begins with a memorial service at Oak Lawn Cemetery in Lake City to honor those who died from both sides on day one and ends with a reenactment at the Olustee Battlefield Historic State Park on day three.

[39] The Alligator Warrior Festival is held each year on the weekend of the 3rd Saturday in October to recognize the early history of Columbia County prior to the Civil War.

Starting in 2010 the annual festival has been held at O'Leno State Park 20 miles (32 km) south of Lake City where the appropriate facilities exist for a full-scale battle reenactment, historic camping and large crowds.

Lake City was a scheduled stop for Amtrak's Sunset Limited between Los Angeles and Orlando from 1993 to 2005, when damage to railroad lines and bridges by Hurricane Katrina caused the curtailment of all service east of New Orleans, Freight service is provided by the Florida Gulf & Atlantic Railroad, which acquired most of the former CSX main line from Pensacola to Jacksonville on June 1, 2019.