D. F. Malan Airport was opened in 1954, a year after Jan Smuts Airport (now O. R. Tambo International Airport) on the Witwatersrand, near Johannesburg, opened. The airport replaced Cape Town's previous airport, Wingfield Aerodrome. Originally named Bellville Airport due to its proximity to the town of the same name, it initially served as a domestic airport. Then, at the request of the Bellville Federation of Taxpayers, the airport was renamed after the then South African prime minister. D.F. Malan National Airport soon achieved international airport status when a direct flight to Britain and a second flight to Britain via Johannesburg was introduced.

With the fall of apartheid in the early 1990s, ownership of the airport was transferred from the state to the newly formed Airports Company South Africa, and the airport was renamed to the politically neutral Cape Town International Airport. South African Airways launched a route to Miami in December 1992. In January 2000, the carrier replaced it with a flight to Atlanta, whose outbound leg from Cape Town included a stop in Fort Lauderdale.

The first years of the twenty-first century saw tremendous growth at the airport; from handling 6.2 million passengers per annum in 2004–05, the airport peaked at 8.4 million passengers per annum in 2007–08 before falling back to 7.8 million in 2008–09. In June 2008, Delta Air Lines started a flight to New York via Dakar. It used a Boeing 767 on the route. Delta began flying to Atlanta instead the following June. The company terminated the route in September 2009. In December 2011, Malaysia Airlines discontinued its service to Buenos Aires.

In 2016, the airport saw a 29% increase in international arrivals; 2016 also saw the airport handle 10 million passengers per annum. United Airlines commenced seasonal flights to Newark on a Boeing 787 in December 2019. The route became year-round in 2022. In October 2023, South African Airways inaugurated a link to São Paulo.

On 16 April 2018, it was reported in the Cape Times that the Minister of Transport, Bonginkosi Nzimande, had directed ACSA on 22 March 2018 to change the name of Cape Town International Airport to Nelson Mandela International Airport. The name change was discussed and as yet no name change had been published in the Government Gazette.

On 5 March 2019, the EFF filed a motion in Parliament calling for Cape Town International Airport to be renamed for anti-apartheid activist Winnie Madikizela-Mandela. Some Khoi activists, meanwhile, argued for the airport to be named after the !Uriǁ'aeǀona translator Krotoa. However, South Africa's Parliament was not constitutionally empowered to enact name changes: the South African Geographical Names Council (SAGNC) held that responsibility. The motion was unsuccessful.

In February 2021, the Cape Times reported that the proposed name change of the airport had been "quietly ditched".

In 2024, CTIA experienced its highest tourism passenger volumes on record. During 2024, the airport processed over 10 million passengers and 75,000 tons of cargo. Despite this, in early 2025, the airport reported even higher transit figures, with an 8% increase in domestic travel, a 5% increase in international arrivals, and a 56% increase in cargo volumes.

In October 2025, it was reported that, based on recent air travel statistics, numerous airlines were choosing to send an increasing number of outbound flights from SA via Cape Town International instead of via Johannesburg's O. R. Tambo International. Reasons include greater efficiency with immigration processing and reduced layover times in Cape Town, compared to Johannesburg.

In March 2026, it was reported that an increasing number of foreign passengers were choosing to travel via Cape Town International, rather than landing at O.R. Tambo (in Johannesburg), when visiting South Africa. CTIA's passenger numbers more than doubled between 2012 and 2026, whereas Joburg's have decreased during the same period. Similarly, while O.R. Tambo's total aircraft figures were roughly the same in 2026 as they were in 2012, those at Cape Town International had tripled over that period. Furthermore, there has been an increase over that period of the number of passengers (average capacity) carried by planes landing at CTIA.

In July 2026, Airports Company South Africa (ACSA) confirmed that the development of a large-scale solar power plant at Cape Town International was well underway. The project is set to have a peak generation capacity of at least 2.5 megawatts (MWp), with the goal of reducing the airport's reliance on the national grid, while also reducing operating costs and carbon emissions. ACSA said airports needed to make these kind of infrastructure investments. Following similar developments at airports in George, Kimberley, and Upington, Cape Town International will become SA's first major airport (international gateway) to have this kind of off-grid power setup.