In the autumn of 1940, a group of local men from the Saranac Lake Planning board got together to discuss the possibility of an airport in the Adirondack Mountains, near Saranac Lake. Their thinking was that such a development would play an important part in the future development of the Adirondacks. Due to the mountainous nature of the region many thought such a development would not be likely. However, after countless reviews of area maps, a plateau large enough for airport purposes was identified within a few miles of Saranac Lake Village.

The Planning Board's search for an airport site had been prompted by an announcement from Washington, D.C., that Congress had appropriated funds for the building of a system of airports throughout the country. There was, among other problems, however, one restriction. The land for an airport site, to be acceptable to the federal government, had to be publicly owned. The ideal site which these men had spotted on the map was part of the holdings of the Paul Smith's Electric Company. Since no other tract of suitable terrain was to be found within a radius of some 40 miles (64 km), the whole effort might have bogged down but for the public-spirited cooperation of the Paul Smith's Electric Company which, in the interests of regional development, immediately deeded the 1,200-acre (4.9 km2) tract to the Town of Harrietstown without cost.

With the requirement of public ownership thus complied with, events moved swiftly toward the realization of an airport for the Adirondacks. Through persistent effort on the part of various citizens, who maintained close contact with Washington, D.C., the site was inspected and federal expenditures for construction of a Class III airport were approved. Step by step, the Town of Harrietstown Town Board and the Saranac Lake Airport Commission worked closely with state and federal agencies in the building process. Construction of the airfield was completed in 1942. The Town of Harrietstown issued bonds to augment the available funds and erected a terminal building in 1948 and a 100 by 100-foot (30 m) hangar in 1950.

At the time, the airport was rated as one of the best built Class III airports in the country. Two commercial airlines, Colonial Airlines and Resort Airlines, served the region at that time. Airmail service was provided by Colonial Airlines. The volume of air express business handled by Railway Express Agency increased steadily, as did the number of privately owned aircraft using the field. Resort traffic response was immediate and increased steadily.

The airport was officially dedicated to the service of the people of the Adirondacks on July 10, 1949. Since 1960, the Town of Harrietstown has operated the airport. The Saranac Lake Airport was renamed in 1989 to the Adirondack Regional Airport.

Commutair, a marketing affiliate of US Air, began serving Adirondack Regional Airport in 1991.

In 2000, the Federal Aviation Administration cited Adirondack Regional Airport for several violations, including failure to conduct monthly fire-and-rescue training and triennial full-scale emergency exercises, faded markings on the taxiway, cracked pavement on runways and the taxi-way, and broken lights. During an inspection in 2001, the Federal Aviation Administration found the violations had not been corrected and, as a result, Adirondack Regional Airport surrendered its certificate allowing larger planes to land at the airport. Repairs began in September 2001.

Commutair ended service at Adirondack Regional Airport in October 2007. Commutair had been flying into Adirondack Regional Airport on 19-seat planes, and Commutair decided to replace all of those planes with larger planes that it decided were too large for the airport.

Big Sky Airlines, a partner of Delta Air Lines, began service at the airport when Commutair ended its service. Big Sky Airlines ended its service to the airport in December 2007, and the airline went out of business several months later.

The United States Department of Transportation invited airlines to bid to serve the airport, and Cape Air was the only airline to bid. Cape Air was a partner of JetBlue and Continental Airlines. Cape Air's service at Adirondack Regional Airport began in 2008.