In 1927, Syracuse mayor Charles Hanna felt his city needed an airport. Land in the Amboy section of the nearby town of Camillus was purchased for $50,000, and by 1928, the "Syracuse City Airport at Amboy" was handling airmail.

With the start of World War II, the airport was pressed into service as a flight training center for the Army Air Forces. By 1942, it had become apparent that Amboy Airport was not large enough to handle military needs, and as a replacement, the AAF opened Syracuse Army Air Base in the suburb of Mattydale, New York. At the end of World War II, the AAF leased the base to the city. On September 17, 1949, the Clarence E. Hancock Airport (named for the area's Congressman) opened to the public using a renovated machine shop as a terminal and replaced the airport at Amboy. The airport had three concrete runways, 5,500 feet (1,700 m) long and 300 feet (91 m) wide.

American, Buffalo, Colonial and Robinson Airlines were the first airlines to operate out of the airport. The April 1957 OAG shows 50 weekday departures: 30 on American, eight on Eastern and 12 on Mohawk. Nonstops didn't reach west past Buffalo or south past New York; Syracuse didn't get a Chicago nonstop until 1967. In the mid-1970s the airport was dominated by Mohawk's successor Allegheny Airlines, with some competition from Eastern and American.

During this time, the airport was expanded several times, becoming the second-largest airport in Upstate New York by passenger volume and the largest by number of flights. At its height, 3.17 million passengers passed through the airport.

Utica-based Empire Airlines emerged as a regional competitor to Allegheny's successor USAir by the early 1980s. Empire planned to move its headquarters to Syracuse, but these plans were cancelled when Piedmont Airlines acquired Empire in 1986. After a legal battle with the city, Piedmont agreed to maintain a hub operation at the airport and advance funds for construction of a new terminal concourse. USAir acquired Piedmont in 1989, becoming the airport's dominant carrier, but dismantled the Syracuse hub in the 1990s, leading to the closure of several gates.

The largest aircraft ever to visit Syracuse was an Antonov Airlines AN-124, which flew a cargo flight from Vienna in 1996. A British Airways Concorde made a scheduled landing at the airport on September 27, 1986.

21st century

In 2013, the airport's two concourses were connected airside along with the opening of a new centralized security checkpoint.

In November 2018, $62 million renovation efforts were completed on Syracuse's terminal. Renovations included larger windows and higher ceilings allowing more natural light, a brand-new flight museum highlighting the history of aviation both locally and globally, renovated passenger bridges connecting the terminal to the parking garage, as well as more "modern" airline check-in areas. The project took approximately eight months to complete.

Southwest Airlines entered the Syracuse market for the first time in 2021 after the airport waived $1.5 million in fees and provided $150,000 in marketing assistance. Syracuse had been the only major upstate New York airport not served by Southwest. Southwest ended service at Syracuse on August 4, 2024, due to aircraft delivery delays.

On March 8, 2022, Breeze Airways began serving the airport.

On June 10, 2022, the airport announced intentions to create its own police department. Previously, the Syracuse Police Department provided police services to the airport with off-duty officers. The new police department began operations on March 6, 2023.

An Escape Lounge opened in June 2023.

While Syracuse has had commercial service to Canada at various times—most recently in October 2018—it does not currently have any scheduled international service.

As of 2022, the airport had several projects in planning or construction. Parking, which has reached capacity during recent peak travel times, is being expanded with new lots and a rebuild of the parking garage into two new garages. Car rental facilities are to be moved from the terminal and parking garage to a new consolidated rental car facility and ground transportation center.

The airport's terminal and its two concourses have seen recent additions of new jet bridges and/or terminal bump outs for hold rooms at Gate 22, 27, 11, and 14. A new U.S. Customs and Border Protection facility has been built in the location of Gate 15 to replace a smaller, outdated one in the Gate 14 area.