In 1940, Wicomico County and the City of Salisbury begun to construct the airport with the Works Progress Administration. It originally encompassed 695 acres and cost $1.5 million. Officially opened on November 11, 1943, Salisbury was originally leased to the U.S. Navy as a training base during World War II up through 1945.

After the war ended, Airfield Operating Corp. leased the airport beginning commercial activity to Easton, Baltimore, and Washington, D.C. Later, in 1949 the City and County resume management of the airport and All American Airways takes over for Chesapeake Airways, later superseded in 1950 by Allegheny Airlines. Numerous improvement projects including runway resurfacing and taxiway lights were installed in the 1960s. Henson Aviation, under contract with Allegheny Airlines and owned by Richard A. Henson, began scheduled commuter service in 1968 and operated with the idea of using "frequency" flights using small aircraft which would shuttle passengers to many airports along the east coast. However, Allegheny discontinued the service in 1969. In 1971, the City of Salisbury relinquishes its interest to the county. In 1978, the Maryland State Police establish a medevac helicopter base.

In 1983, Henson Aviation was purchased by Piedmont Airlines and began operating as Henson, The Piedmont Regional Airline. Henson Airways reigned as the primary air service provider in Salisbury until US Airways Express purchased Henson Aviation in 1993. After the merger, the airline was renamed Piedmont and it deemed Salisbury as its primary operating base and quickly grew into a large regional carrier. After opening the base, the airline operated flights to Philadelphia and Washington. A few years later, Piedmont opened a new hub in Charlotte, North Carolina which rapidly grew to become larger than its hub in Washington, D.C. The service to Washington was later cancelled and was replaced with service to Charlotte..

In 2017, the airport re-branded itself SBY Regional Airport.