In August 1928 a property in Vandalia, Ohio was called the "Dayton Airport".

The layout of four proposed 100-foot (30 m) wide paved runways – 4,000-foot (1,200 m) east-west, 3,400-foot (1,000 m) northeast-southwest, 3,400-foot (1,000 m) northwest-south east and 2,400-foot (730 m) north-south – was unveiled in February 1936. Construction began in mid May, the design of a terminal with a 7,520 sq ft (699 m2) footprint was approved in early October and the first transport plane to land on one of the new runways arrived on a test run in late November. The airport opened on 17 December 1936. By June 1937, the north-south runway had not been built.

The Northwest-Vandalia Modification Center began operations in July 1943 in eight large cinderblock hangars that had been built at the airport. At the same time, the runways were widened to 150 feet (46 m).

In October 1952, the city named the airport James M. Cox Dayton Municipal Airport in honor of the former Governor of Ohio and Democratic candidate for President of the United States. A groundbreaking ceremony was held in 1959 for a new $5.5 million terminal designed by Yount, Sullivan and Lecklider, completed in 1961.

The April 1957 OAG shows 73-weekday departures: 56 TWA, 13 American, and 4 Lake Central. TWA had two nonstops to New York but no other nonstops reached beyond Chicago-Detroit-Cleveland-Pittsburgh-Cincinnati. The first jets were TWA Convair 880s from Chicago in January 1961.

The eight former modification center hangars were torn down in 1966.

The facility was renamed James M. Cox Dayton International Airport in April 1976 and the first international flight landed two months later.

The airport was a hub for Piedmont Airlines from July 1, 1982, until its merger with US Airways, which continued the Dayton hub for a year or two. In March 1988 Piedmont had nonstops from Dayton to 27 airports, California to Boston to Florida, plus eight more on its prop affiliate. USAir and successor US Airways kept Dayton as a focus-city. The airport was a hub for Emery Worldwide, a freight carrier.

In 1981 Emery Worldwide completed an air freight hub sortation facility next to Runway 6L–24R. Emery added to the facility until the early 1990s, making it one of the world's largest airfreight facilities at the time.

A $50 million renovation of the airport's terminal building, designed by Levin Porter Associates, was completed in 1989. A new two-lane access road was built.

In 1998 the airport started renovating the terminal building. The $25 million projects was completed in 2002. The renovations included energy-efficient climate control systems, lighting, windows and entry/exit doorways, a new paging system, and ceiling tiles and carpeting. The news, gift shops, and food and beverage concessionaires improved their leased areas in the terminal building.

In 2004, CNF (which had acquired Emery Worldwide in 1989) sold its Menlo Forwarding business to UPS, who operated the Menlo freight facility at Dayton as an air cargo hub and sorting center.

In June 2006, UPS ceased operations at the Menlo cargo facility, consolidating its cargo operation and sorting facility to its Louisville hub, and reducing cargo tonnage through the Dayton airport by 97% from its 2005 peak

On May 1, 2011 Air Canada Express ended flights to Toronto Pearson, the airport's only international destination, when the airline consolidated its service at Cincinnati/Northern Kentucky International Airport. Dayton now has no scheduled international flights.

On August 12, 2012 Southwest Airlines began serving Dayton with flights to Denver International Airport. This was expected to increase passenger traffic by at least 15 percent.

In 2013 Concourse D, built in 1978 and used by Piedmont Airlines and US Airways for their mini-hub operation until its closure in 1991, was demolished. Concourse C was renamed Concourse A.

In 2015 Southwest Airlines announced a reduction in flights from Dayton: nonstop flights to Baltimore, Denver, Orlando, and Tampa all ended April 11, 2016. This left one nonstop destination from Dayton via Southwest. Passenger traffic is down nearly 9% since 2014, along with aircraft departures down 8%. Fares from Dayton have continued to rise while neighboring airports are lowering fares with new low-cost carriers. Cincinnati/Northern Kentucky International Airport has drastically reduced fares since 2014 while also experiencing over 10% growth in passengers.

On November 19, 2015, Dayton officials announced that Allegiant Air would add service in April twice a week to Orlando and Tampa. Allegiant Air would become the only low-cost fare carrier at the airport and would fill the gap left by Southwest Airlines reduction in flights to Florida.

On January 4, 2017, Southwest announced that it would end its flights to Chicago Midway and move services to Cincinnati/Northern Kentucky International Airport, adding eight daily flights to and from Chicago Midway and Baltimore–Washington International Airport.