In the 1920s and 1930s, Dakar was originally served by Ouakam Airfield, which operated airmail services and civilian transport by Air France. By 1943, the airfield was too small for heavy aircraft, and was unable to handle growing air traffic. In 1944, Mullard Airfield (now Dakar Airport) was established. By the 1960s, French Air Force operations were relocated from the old airfield to Mullard Airfield.

During World War II, Dakar Airport was a key link in the United States Army Air Forces Air Transport Command Natal-Dakar air route, which provided a transoceanic link between Brazil and French West Africa after 1942. Massive amounts of cargo were stored at Dakar, which were then transported along the North African Cairo-Dakar transport route for cargo, transiting aircraft and personnel. From Dakar, flights were made to Dakhla Airport, near Villa Cisneros in what was then Spanish Sahara, or to Atar Airport, depending on the load on the air route. In addition to being the western terminus of the North African route, Dakar was the northern terminus for the South African route, which transported personnel to Pretoria, South Africa, with numerous stopovers at Robertsfield (now Roberts International Airport), Liberia, the Belgian Congo and Northern Rhodesia.

Before the introduction of long-range jets in the mid-1970s, it was an important stopover point for the routes between Europe and South America, along with the Canary Islands.

From 21 January 1976 to 31 March 1982, Air France Concordes used the airport as a refueling stop between Paris and Rio de Janeiro on Wednesdays and Sundays.

The airport was a Space Shuttle landing site until 1987, when it was determined that a dip in the runway could damage the shuttle upon landing.

It was one of the five main hubs of the now defunct multi-national airline Air Afrique.

Aeroflot used to serve the airport from the 1970s, it flew the Moscow-Dakar route with stopovers midroute. In the 1990s, Aeroflot replaced the route with a nonstop flight from Moscow to Dakar. However, this service was terminated somewhere around 2000. Marking the end of the airline’s 3 decades-long presence in the airport.

The airport has often been used as a stopover on flights between North America and Southern Africa. Delta Air Lines started service on 4 December 2006 between Atlanta and Johannesburg, with an intermediate stop in Dakar. This stopover has since been removed, with Dakar now served nonstop by Delta from New York–JFK. South African Airways used Dakar as a stopover with both its flights from Johannesburg to Washington and New York. The stopover for the New York–JFK flight was later removed, while the Johannesburg to Washington–Dulles flight now operates via Accra.

Senegal Airlines had a hub operation and their headquarters at the airport before the company's demise in April, 2016.

Construction of a replacement airport, Blaise Diagne International, 45 kilometres (28 mi) inland from Léopold Sédar Senghor, began in 2007. Saudi Binladin Group constructed the new airport, named after the first black African elected to France's parliament in 1914, Blaise Diagne. It was initially expected to take 30 months to build and is designed for an initial capacity of 3 million passengers a year – almost double the 1.7 million annual traffic handled by the existing airport. Blaise Diagne was delayed several times and finally opened on 7 December 2017. As of March 2020 Senghor Airport serves only charter flights and scheduled cargo services, but not regular passenger flights.