In 1939, the Army sent Major George C. Kenney to Puerto Rico to conduct a preliminary survey of possible air base sites on Puerto Rico. He examined 42 sites and declared that Punta Borinquen the best site for a major air base. In September 1939, the government purchased 3,796 acres (1,536 ha) of sugar cane farms for military use, for $1,215,000. Later that year, Major Karl S. Axtater assumed command of what was to become Borinquen Army Air Field.

With the establishment of an independent United States Air Force in 1947, the complex was renamed Ramey Air Force Base in 1948. Ramey AFB was home to a Strategic Air Command bombardment wing and housed a number of B-36 Peacemaker intercontinental bombers. The B-36s were later replaced by B-52 Stratofortress heavy bombers and KC-135 Stratotanker aerial refueling aircraft.

A tenant weather reconnaissance squadron operated WB-47 Stratojet and WC-130 Hercules aircraft. Due to the size and weight of the B-36, the runway at Ramey had to be built to a length of 11,702 feet (3,567 m) and a width of 200 feet (61 m), added an 870 feet (270 m) Blast Pad at each end and a 50 feet (15 m) shoulder on each side.

In 1971, the closure of what became Ramey Air Force Base began and lasted until 1973. Following its closure, it was converted into a civilian airport. It used to receive domestic commercial flights by Prinair and Vieques Air Link as well as service from New York JFK with Capitol Air, and Boeing 720 passenger flights from Miami operated by Southeast Airlines. It is also noted for being the place that the large clothing company, Wrangler Jeans, used to land their planes filled with company-related cargo as part of their airline operation, Wrangler Aviation, which was later renamed to Sky Lease Cargo.

In the mid and late 1970s, the Ahrens Aircraft Corporation attempted to set up operations at former USAF industrial facilities at the airport in order to manufacture the Ahrens AR 404 regional airliner, a short takeoff and landing (STOL) turboprop aircraft, with financial incentives promised by the Puerto Rican government for development. A government investigation over these incentives ensued and the project was cancelled after only two AR 404s were built at Rafael Hernández Airport.

In 2004, the Puerto Rico Ports Authority announced that it would be remodeling and expanding BQN to accommodate more flights and passengers. An expansion of the terminal building and a new parking lot were opened in July 2005.

Since the closure of Ramey AFB in 1974, the airport's control tower had remained standing, but was non-operational, limiting the airport to UNICOM communication as an uncontrolled airport. Following refurbishment of the former USAF control tower in 2006 and 2007, the newly renovated control tower became operational in July 2007.

In February 2012, the mayor of Aguadilla and the U.S. Secretary of Commerce designated the airport a "free trade zone" (FTZ), as are many other airports in the U.S., to improve the development of the airport and surrounding areas.

In April 2014, Lufthansa Technik announced the creation of a maintenance, repair and overhaul center (MRO) at the airport. This created operations for maintenance of Lufthansa Aircraft flying on the Americas, starting with 2 reconditioning lines by C and D checks for the Airbus A320, with plans to expand up to 5 reconditioning lines.

Passenger service

In 1988, Carnival Airlines and ATA began passenger jet service. In the 1990s, American Airlines, joined those two airlines, followed by Pan Am II and TWA. Carnival Airlines operated Airbus A300 wide-body jet service to New York JFK, Neward and Fort Lauderdale. In the early 1990s, Carnival Airlines operated the first intra-Puerto Rican jet service from the airport to Ponce with Boeing 727s as well as with wide body Airbus A300s.

Another carrier, Prinair previously conducted operations at Rafael Hernández Airport. North Cay Airways provided passenger air service from San Juan at some time during the airport's history. In 1995, American Airlines was operating daily nonstop Boeing 757-200 jet service to New York JFK airport. Carnival Airlines flew nonstop to JFK at this same, with Boeing 727-200 jet service three days a week.

In 2000, North American Airlines had reopened passenger service with a non-stop flight to New York JFK three times a week. Later, Continental Airlines joined North American with a daily flight to their hub in Newark. Continental has since merged with United Airlines, and the latter airline has continued to provide service. Boston-Maine Airways operating as Pan Am began jet service to Orlando Sanford International Airport in Florida and to Santo Domingo.

In 2005, JetBlue began a daily flight to their hub at New York JFK. Soon after the arrival of JetBlue, North American ceased operations. As a result, JetBlue announced that it would add a second daily flight to New York JFK.

In 2006, Delta Connection began regional jet service to Atlanta, Georgia, five times a week, although this service ended on January 20, 2007, as part of Delta's restructuring plan.