On July 2, 1927, twelve P-1 aeroplanes under the command of Major Thomas G. Lanphier, Air Corps, proceeded from Selfridge Field to Ottawa, acting as Special Escort for Colonel Charles Lindbergh, who was to attend at the opening of the Dominion Jubilee. First Lieutenant J. Thad Johnson, Air Corps, commanding 27th Pursuit Squadron, was killed in an unsuccessful parachute jump after a collision with another plane of formation in a demonstration on arrival over Ottawa. There is now a street leading to the airport industrial section named after the aviator.

The airport was opened at Uplands on a high plateau (then) south of Ottawa by the Ottawa Flying Club, which still operates from the field. During World War II, when it was known as Uplands, the airport hosted No. 2 Service Flying Training School for the British Commonwealth Air Training Plan, providing advanced pilot training in Harvard and Yale aircraft.

In 1950, to allow for a southward expansion of the airport, the nearby farming community of Bowesville, settled in 1821, was expropriated. The last residents left and the village school was torn down in 1951. The current main airport terminal now stands on the site of the crossroads at the centre of the village. The road to the south of the airport still bears the name "Bowesville Road".

During the 1950s, while the airport was still named Uplands and a joint-use civilian/military field, it was the busiest airport in Canada by takeoffs and landings, reaching a peak of 307,079 aircraft movements in 1959, nearly double its current traffic. At the time, the airport had scheduled airline flights by Trans-Canada Air Lines (Toronto, Montreal, and Val-d'Or), Trans Air (Churchill), and Eastern Air Lines (New York via Syracuse and Washington via Montreal). With the arrival of civilian jet travel, the Canadian government built a new field south of the original one, with two much longer runways and a new terminal building designed to handle up to 900,000 passengers/year.

The terminal building had been scheduled to open in December 1959, but during the opening ceremonies, a United States Air Force F-104 Starfighter went supersonic during a low pass over the airport, and the resultant sonic boom shattered most of the glass in the airport (including the entire north wall) and damaged ceiling tiles, door and window frames, and even structural beams. The total cost of the damage exceeded $500,000, and the opening was delayed until April 1960. George Hees, the Canadian Transport Minister, stated that "the sonic explosion subjected the terminal building to five times the hurricane force which it had been designed to withstand". The incident has been described as "the most expensive five seconds in Canadian civil aviation history". The original terminal building and Trans-Canada Airways/DOT hangar continued in private use on the airport's north field as a location for the Ottawa Flying Club until the fall of 2011 when it was demolished.

The airport was renamed "Ottawa International Airport" in 1964. It became "Ottawa Macdonald–Cartier International Airport" in 1993.

In the 2000s, the original terminal was entirely replaced and expanded by more modern facilities.

In 2017, the Canada Border Services Agency started to use facial recognition technology to process incoming international travellers. All international passengers are directed to Primary Inspection Kiosks before seeing a Border Services Officer and are no longer required to fill out a declaration card.

On November 1, 2022, Porter Airlines and the Ottawa International Airport Authority announced they would be investing over $65 million at the airport in the future. Porter also announced they would be building two aircraft hangars at a size of over 14,000 m2 (150,000 sq ft) each, to maintain the Embraer E195-E2 and Bombardier Dash 8 aircraft. These will be built in two phases, with phase one being completed by the end of 2023 and phase two in the first quarter of 2024, making the airport the primary E195-E2 maintenance base and creating 200 local jobs.