On June 1, 1929, the city of Saskatoon was given a "Licence For Air Harbour" and the airport was established. This provided a home for the Saskatoon Aero Club.

From 1940 to 1947, the city leased the airport to the Royal Canadian Air Force (RCAF). The airport became RCAF Station Saskatoon. The station was a part of the British Commonwealth Air Training Plan, and the station was home to No. 4 Service Flight Training School. To support these operations, four large hangars were built, as well as support buildings, which included a hospital and control tower.

After the war (1947) the airport was transferred to the Canadian Department of Transport for civilian use. The same year,Trans-Canada Air Lines, now known as Air Canada, started to provide passenger service using Douglas DC-3 aircraft.

Air Canada in 1950 began operating the Canadair North Star at the airport, followed by the Vickers Viscount in 1955. A new terminal building was also constructed in 1955 by Transport Department architects.

The primary runway (09/27) was lengthened in 1954 and again in 1960 to 8,300 ft (2,530 m). The secondary runway (15/33) was lengthened in 1963 to 6,200 ft (1,890 m).

From 1950 to 1978 the Airport was again made a station of the RCAF. The station was named RCAF Station Saskatoon.

On January 1, 1971, the City of Saskatoon annexed the airport and surrounding lands totalling 2,111.7 acres. The nearby area, which contained personnel housing and support services, was annexed by the city in 1965.

In 1972, due to larger aircraft and more frequent flights, plans were drafted for a new terminal building. The new terminal built by Holiday and Scott was completed and opened on November 29, 1975. The former terminal was renovated in 1977. From 1977 to 1984, Boeing 747 charter flights were operated by now-defunct Wardair to Europe until Wardair was bought by Canadian Airlines International.

In 1993 the name of the airport was changed to recognize Canada's 13th Prime Minister, John Diefenbaker. In 1995, under the Canada-US Open Skies agreement, Northwest Airlines started service to Minneapolis – Saint Paul. In 1996, WestJet began Boeing 737 service. In 1999, the airport was turned over to the Saskatoon Airport Authority, as part of the National Airports Policy.

In 2000, Nav Canada constructed a new control tower and the airport authority began renovations and expansions to the terminal building. In October 2002, the first two phases of renovations to the air terminal building were completed at a cost of $18 million, designed by Kindrachuk Agrey Architects. The updated terminal facilities were designed to handle 1.4 million passengers annually. In 2005, additional renovations were completed to the check-in area and baggage screening, as well as the addition of a fifth bridge. In 2006, the airport expanded public parking to 500 stalls. In March 2008, work started on the rehabilitation of runway 09/27, taxiway Foxtrot and Alpha at a cost of $16 million.

Between October 2005 and May 2008, Air Canada ended "mainline" service into Saskatoon, turning over routes to Air Canada Jazz. In 2006, Pronto Airways started operating at the airport. In 2006 Transwest Air introduced service to Fort McMurray, Alberta. For a short period of time between 2006 and April 2007, Northwestern Air also operated flights to Fort McMurray. In 2008, United Airlines began non-stop regional service from Denver that operated until 2015. In 2009, United Airlines announced regional service from Chicago that operated until 2014.

In March 2015, Missinippi Airways began thrice-weekly service to Saskatoon direct to Flin Flon, Manitoba, with a one-stop connection to The Pas, Manitoba, though this ceased three months later. In June, 2016, New Leaf Airlines announced they would begin flying to Kelowna and Hamilton direct from Saskatoon twice weekly beginning July 27, 2016, but this lasted just four months before in November of that year.