It is unclear when Karachi Airport was first used by civil aircraft, as it is often confused with RAF Drigh Road, but a location northeast of the RAF station was identified on a 1928 map of Karachi as a landing site for Imperial Airways.

Imperial Airways was one of the first airlines to fly to Karachi, on 30 March 1929, when the territory was part of British India.

J. R. D. Tata made the inaugural airmail flight from Juhu Aerodrome in Bombay (now Mumbai) to Drigh Road airstrip (now Jinnah International Airport), Karachi, via Ahmedabad, on 15 October 1932, carrying mail in a Puss Moth aircraft.

During the late 1920s and early 1930s, a large airship hangar was constructed at the site of Karachi Airport for the British HMA R101. Only three such hangars were built worldwide to accommodate Britain's fleet of passenger airships. The R101 never arrived in Karachi, as it crashed and exploded eight hours into its maiden flight over Beauvais, France, killing all but six of its 54 passengers and crew. The hangar served as a visual navigation marker for aircraft attempting VFR landings at Karachi. Construction began in 1927 and was completed in 1929. In 1952, the Government of Pakistan decided to demolish the structure for scrap metal; demolition was carried out in 1961, with the steel used in railway construction.

The mast was never used, but the hangar served Imperial Airways Handley Page H.P.42s and A.W.XV Atalantas. On 5 December 1938, the Governor of Sind opened a permanent terminal building (now Terminal 1), which featured a circular central hall and two wing sections.

During World War II, Karachi Airport served as a major transhipment base for United States Army Air Forces units and equipment supporting the Tenth Air Force in eastern India, Burma and the Fourteenth Air Force in China. Several operational bomber and fighter units passed through Karachi before deployment. Air Technical Service Command maintained extensive facilities where aircraft were received, assembled and tested prior to onward deployment. The airport also functioned as a major maintenance and supply depot. Air Transport Command operated numerous cargo and passenger flights to the Middle East and to points within British India and China.

In 1953, following the crash of a De Havilland Comet, Karachi Airport closed temporarily and commercial flights were relocated to PAF Base Masroor.

On 25 January 1961, Runway 07L/25R was inaugurated by Finance Minister Mohammad Shoaib. The runway measured 10,500 feet in length and was constructed at a cost of Rs 28 million by employees of the US Corps of Engineers and the Vinnel Corporation. At the time, the airport was served by 13 international and domestic airlines.

On 3 November 1972, it was announced that Karachi International Airport would be expanded in two phases to meet rising passenger volumes. The first phase covered international arrival areas, the existing transit lounge and domestic areas, expected to be completed by October 1973. The second phase included a new international departure-cum-transit lounge and a car park, with capacity for 600 departure and transit passengers and an enlarged arrival lounge accommodating over 320 passengers.

In 1978, Terminal 2 was built by Pakistan International Airlines to relieve congestion. The terminal measured 130 metres in length, contained two departure lounges accommodating 577 and 50 first class passengers respectively, could serve four wide-bodied aircraft simultaneously, cost 10 million Pakistani rupees and was designed to last 60 years. By that time, the airport was served by 29 airlines.

In February 1984, a fire severely damaged Terminal 2; Terminal 1 remained operational throughout. Construction of Terminal 3 followed in the late 1980s. The Jinnah Terminal began construction in January 1989 and was completed in June 1991 after approximately two years of construction and four years of planning, opening to the public in August 1992. The planned expansion — which envisaged expanding the terminal to three times its original size with four satellite terminals, 32 gates and an annual capacity of eight million passengers — was not completed. An expansion programme in 1994 extended Runway 07R/25L from 7,500 feet to its current length of 11,155 feet. The Jinnah Terminal now handles both domestic and international flights; Terminal 2 is dedicated to Hajj operations; Terminal 1 houses the headquarters of the Civil Aviation Authority; and Terminal 3 is used for commercial offices. Following completion of the Jinnah Terminal, the airport was renamed Quaid-i-Azam International Airport.

In approximately 1992–93, Karachi Airport handled 2,766,449 international passengers and 2,570,827 domestic passengers.

Between the 1960s and 1980s, the airport served as an online station for airlines including BOAC, Qantas and Pan Am, featuring prominently on Eurasia routes. In March 2006, Pakistan International Airlines began a non-stop service to Toronto on Boeing 777 aircraft.