Construction began on June 15, 1941, when the facility was still part of Kelly Field. Within a year it split off as the San Antonio Aviation Cadet Center, teaching future pilots the physics of flight, deflection shooting, and three-dimensional thinking before sending them to primary flight schools. On February 3, 1948, it was renamed Lackland Air Force Base after Brigadier General Frank Lackland, who had been commissioned into the regular Army from the District of Columbia National Guard. The Korean War sent training populations soaring -- 28 basic military training squadrons ran simultaneously, and 129 temporary 'I dormitories' were thrown up to replace tent cities housing recruits. The Vietnam War forced a 'split-phase' training experiment in 1965: 22 days at Lackland, 8 days at a tech school. By 1966, a meningitis death and ten confirmed cases shut down non-essential gatherings and forced the activation of a secondary training school at Amarillo Air Force Base.

Basic military training is Lackland's signature, but the base also runs some of the military's most specialized programs. The 341st Training Squadron trains military working dogs and their handlers for the entire Department of Defense and several federal agencies. On October 28, 2013, the Military Working Dog Teams National Monument was unveiled next to the BMT parade field, authorized by Congress and signed into law by President George W. Bush. The 342nd Training Squadron trains pararescuemen, combat controllers, special reconnaissance operators, tactical air control party airmen, and survival, evasion, resistance and escape specialists. The 343rd runs a 13-week Security Forces academy. The 344th processes more than 10,000 students annually across career fields from cryptology to contracting. The base also hosts the Inter-American Air Forces Academy, which teaches 37 technical courses in Spanish and English to students from more than 22 countries.

Visitors approaching Lackland's parade grounds encounter a collection of iconic military aircraft on static display as part of the USAF Airman Heritage Museum. A Boeing B-52 Stratofortress stands alongside a Lockheed SR-71 Blackbird, a Boeing B-29 Superfortress, a McDonnell Douglas F-4 Phantom II, a Boeing B-17 Flying Fortress, a Lockheed C-121 Constellation, and a North American B-25 Mitchell. The aircraft span decades of American air power, from the World War II-era B-17 to the Cold War's SR-71. When adjacent Kelly Air Force Base closed in 2001, Lackland absorbed its two-mile-long runway, now a joint-use facility shared with Port San Antonio. The former Kelly grounds brought flying units including the 433rd Airlift Wing with its C-5 Galaxy transports and the 149th Fighter Wing of the Texas Air National Guard flying F-16 Fighting Falcons. Lackland also inherited Security Hill, home to cyber warfare and intelligence units.

In the winter of 2009, the decision was made to merge all of San Antonio's military bases into a single entity. On October 1, 2010, Lackland joined Fort Sam Houston and Randolph Air Force Base to form Joint Base San Antonio, one of 12 joint bases created nationwide under the 2005 Base Realignment and Closure legislation. In March 2020, the base's Medina Training Annex was renamed Chapman Training Annex after Medal of Honor recipient Master Sergeant John A. Chapman. In December 2017, the Kelly Field Annex was renamed simply Kelly Field to mark the 100th anniversary of the airfield becoming government property. Today Lackland sprawls across four distinct sections: the Kelly airstrip, Security Hill, main base Lackland, and Chapman Training Annex. More than 24,000 retirees live in the local area, and the base remains the single gateway through which every new Air Force and Space Force enlisted member enters service.