Eugenio María de Hostos Airport used to be the main air gateway to the western region of Puerto Rico, until Rafael Hernández Airport in Aguadilla took over that position.

The airport was served during the 1960s from San Juan by Caribair, and then, rather heavily, by the Puerto Rican national air carrier, Prinair, during the 1970s and early 1980s. At one point, Prinair served Las Americas International Airport in Santo Domingo, Dominican Republic with De Havilland Heron aircraft from Mayaguez, making the airport an international one. It took the airport three years to get commercial service again after Prinair went bankrupt in 1984. American Eagle opened service from Luis Muñoz Marín International Airport in 1987, and Eastern Air Lines, not to be outdone by their rival American's feeder carrier, soon began services there too, with their own feeder airline, Eastern Metro Express.

Although the airport has always been a turbo-prop aircraft airport, Pan Am announced, in 2002, intentions to install jet flights between Mayagüez and Las Américas International Airport in Santo Domingo, Dominican Republic, with Boeing 727s. Those plans never became a reality, but in 2003, the airport regained its international status, when Fina Air picked up the route to Santo Domingo. Fina Air has since gone out of business.

On November 8, 2004, American Eagle filed a 90-day notice of intent to the DOT to end service to Mayagüez on February 5, 2005 due to poor loads. MAZ is an Essential Air Service market therefore American Eagle's service was extended by the DOT until the newly selected carrier, Cape Air, began operations. American Eagle ended operations on April 30, 2005.