Built in 1928 on 260 acres (1.1 km2) of land along U.S. Highway 41 and funded by a city bond issue, the original airport had a small terminal, weather bureau, hangar, runways, boundary lights, grading, and drainage.

On June 16, 1930, the Evansville Municipal Airport was dedicated. The runways, 100 × 1,200 feet and four inches thick, cost $30,000. The first airport manager was Werner J. Genot, who took charge on December 16, 1930.

Interstate Airlines stopped at Evansville on their Chicago–Atlanta and St. Louis – Louisville routes on October 19, 1928. Also in 1928, Capital Air Corporation started passenger flights through Evansville. The airport did not have an airline from February 1933 until 1940, when Eastern Airlines started two departures a day. Plans were made for expansion.

In 1950 a new terminal opened at a cost of $787,000. The Evansville city council passed an ordinance to change the name of the airport to Dress Memorial Airport on October 11, 1950, and on October 29, 1950, the new terminal was dedicated. The airport property now covered 467 acres; 347 acres was used for aircraft operations and 120 acres was used for agriculture.

The first jet at the Evansville airport landed in September 1964, a chartered 727 carrying presidential candidate Barry Goldwater.

The original terminal was replaced in 1988 with the new William H. Dress Terminal, designed by Hafer Associates with 140,000 square feet (13,000 m2) and ten gates.

In January 2012, the airport announced the adding of four new jet bridges. At the beginning of 2013, the jet bridges were installed. This allowed passengers to avoid having to exit the terminal and board the plane from the outside. It was the first time that Evansville Regional Airport had new jet bridges, since USAir exited the Evansville market in the 1990s. A subsequent ribbon cutting took place at the airport on January 17, 2013.

In the 2010s, the airport began to see passenger growth. In response to this, on August 20, 2014, Delta Air Lines upgraded to a Boeing 717 with daily service to Atlanta. Delta further upgraded to a McDonnell Douglas MD-88 at the beginning of summer in 2015, in addition with current 717 service, occasionally replacing the smaller aircraft on some flights. Currently Delta runs the 717 service for its first flight out of Evansville and its late flight into Evansville. Delta has recently stopped their 717 service in Evansville due to aging aircraft, but has replaced that aircraft with the Bombardier CRJ-900 for its Atlanta service. Also, on October 2, 2014, American Eagle began daily service to Charlotte using a Bombardier CRJ-200. On June 4, 2015, United Express began three daily flights to O'Hare International Airport in Chicago utilizing the Embraer ERJ-145. Currently American Eagle uses an Embraer 175 for its Dallas-Fort Worth service.

After further growth and expansion at the airport, the Vanderburgh Airport Authority approved the construction of a fifth jet bridge in Concourse A. Furthermore, on June 2, 2016, Allegiant Air began flights to Orlando/Sanford, operating two weekly flights on Sunday and Thursday utilizing the McDonnell Douglas MD-80. The flights are now operated on Airbus A320 aircraft.

On November 8, 2021, Evansville Regional announced that United Airlines was pulling their daily flights to Chicago. Evansville was one of 15 other airports that United pulled service from.

On March 3, 2022, Evansville Regional announced American Airlines has paused their daily Chicago flights. With this pause, Evansville has no direct flights to Chicago. Days later it was also released that Delta has suspended their Detroit service from Evansville for an undetermined amount of time.

On November 8, 2023, it was announced beginning in February 2024 Breeze Airways will begin twice weekly air service to/from Orlando International (MCO) making this the second Orlando flight service for the Evansville Regional Airport.

On September 4, 2024, American Airlines resumed their flights to Chicago, ending two and a half years of no direct air service linking Evansville with Chicago.