The airport began service in December 1964. It was served by American Airlines from New York City on a JFK–LIM–CUZ–LIM–JFK routing from 1998 to 1999 using Boeing 757-200 aircraft. However, these flights were discontinued due to a number of factors, including the airport's limited services and facilities, as well as the Peruvian government's refusal to grant passenger transportation rights between Lima and Cusco. American still holds the rights to this route and can resume flights at the company's discretion. The airport was largely controlled by airline giants Aeroperú and Faucett Perú, which would both be declared bankrupt in the late 1990s. In 1970, LANSA Flight 502 crashed after taking off from the airport and killed 99 out of the 100 on board.On February 3, 2017, President Kuczynski announced the beginning of the construction of the new Chinchero International Airport, which will be located in the suburb of Chinchero, 30 minutes from the city of Cusco. It is estimated that the new airport, will be completed by 2025 when Velasco Astete International Airport will be closed. It is expected to receive up to 6 million passengers upon its opening. Its main intent is to promote more tourism in Cusco and to prevent a stop in Lima's Jorge Chávez International Airport, since the current airport mostly has domestic destinations from Lima and other countries in South America. There are multiple environmental and safety concerns regarding the new airport, with numerous attempts, even by UNESCO, to stop the construction of the airport which could harm the popular Incan site Machu Picchu and other ruins. The new airport broke ground in November 2021.

In November 2025, it was announced that the airport will operate flights to Argentinian cities including Puerto Iguazú, Rosario, Mendoza, Salta, Córdoba, Tucumán and Neuquén. These destinations will be served by LATAM in 2026.