Brownsville was once the main terminal for air service between the United States and Mexico. In 1929, Pan American World Airways acquired a controlling stake in Mexicana de Aviación and began Ford Trimotor service between Brownsville and Mexico City, eventually extended to the Yucatan Peninsula to connect with Pan Am's Caribbean route network. On March 9, Charles Lindbergh inaugurated this service, landing at BRO after a five-hour, 38-minute flight from Mexico City. An event was held on site in Lindbergh's honor, with a crowd of over 20,000 greeting him upon his arrival. Among the attendees was Amelia Earhart, for whom the main street in front of the Airport is named. Brownsville became an early center for technical development in instrument navigation ("blind flying") due to the bad weather conditions that pilots encountered in the mountains over Mexico.

Pan Am's service terminated in Brownsville, and passengers were initially taken on the Missouri Pacific Railroad to St. Louis, Missouri for rail connections to the northern US. In 1931, American Airways was flying a multi-stop route Brownsville to Dallas, connecting to Chicago, Los Angeles and other cities. Braniff Airways began service in 1934, and Eastern Air Lines arrived in 1939.

During World War II the airport was redubbed Brownsville Army Air Field and used by the military for pilot training, engine testing and overhauls.

In 1947, Pan Am's Mexico City route extended to Houston, and Brownsville was an intermediate stop. Pan Am service to Brownsville ended in 1962 as the Mexico City flight became a nonstop service from Houston Hobby Airport eventually flown with a Boeing 707. In the 1960s, the 16th weather radar system in the country was installed at BRO.

In 1979, the year after airline deregulation, Brownsville was served by three airlines: Braniff International Airways (727s to Dallas/Fort Worth), Texas International Airlines (DC-9s to Houston and McAllen), and Tejas Airlines (commuter turboprops to Corpus Christi, McAllen and San Antonio).

In 1982, a new ATC tower was built.

In 1983, the airport was renamed the Brownsville-South Padre Island International Airport.

In 2014, expansion of the runway to 10,000 or 12,000 feet (3,000 or 3,700 m) was proposed by the Brownsville City Aviation Director, and the city purchased 8.2 acres (3.3 ha) of land for about $200,000.

A new modern and more spacious terminal was built in 2019-2020, replacing the old, crowded terminal.

In 2021, in part as a response to expanding operations by SpaceX in relation to its South Texas launch site, a new 91,000 square foot terminal was opened to accommodate an increase in tourism and migration. A further $1.6 million was awarded to the city of Brownsville by the Federal Aviation Administration to enhance the airport's jet bridges. Since March 2022, one of Starship SN8's flaps has been on public display at Brownsville/South Padre Island International Airport.

A new long term parking lot was completed in 2024.