In 1933 Pacific Seaboard Air Lines' single engine Bellanca CH-300s flew twice daily each way: Los Angeles - Santa Barbara - Santa Maria - San Luis Obispo - Paso Robles - Monterey - Salinas - San Jose - San Francisco. Pacific Seaboard later moved its operation to the eastern U.S., was renamed Chicago and Southern Air Lines, and became a large domestic and international airline that in 1953 was acquired by and merged into Delta Air Lines.

Earl Thomson, along with his brothers-in-law, William "Chris" and David Hoover, talked county officials into leasing them the land for an airport. By April 1939 it opened with an 88-by-100-foot (27 by 30 m) hangar and dirt runways.

During World War II the federal government took over the airport: From 1938 until 1941, the U.S. Army Air Corps and the California National Guard used 218 acres as an aerial observation training center; In 1940 the War Department added hard surface runways and lights, barracks, hangars, and mechanic shops. In 1940 and 1941, 183 private pilots and 20 advanced students were trained here though a federally sponsored Civilian Pilot Training Program for armed services fliers. In 1943, the Navy began using the airport as a training center for the Pacific Fleet, calling the airport Naval Outlying Field, San Luis Obispo and the Naval Auxiliary Air Station, San Luis Obispo.

The federal government turned the airport back to the county in 1946. Southwest Airways started passenger flights with Douglas DC-3s that year.

Southwest's flights to San Luis Obispo ended in 1956 when the airline moved to Paso Robles Municipal Airport in northern San Luis Obispo County due to the 4000-ft runway at San Luis Obispo being too short for larger aircraft such as the Martin 4-0-4 and Fairchild F-27. Pacific Air Lines, Air West and Hughes Airwest, successors to Southwest Airways, listed San Luis Obispo in their timetables but actually served Paso Robles with F-27s until 1974.

In 1947 county supervisors contracted for another hangar, ramp, and eventually an administration building. The supervisors named Chris Hoover full-time airport manager in 1953.

San Luis Obispo Airport had no scheduled airline service from 1956 until 1969 when locally based Swift Aire Lines began scheduled flights with Piper Navajos. Swift Aire's headquarters were at San Luis Obispo; it eventually operated Fokker F27 Friendships bought new from Fokker as well as Nord 262s and de Havilland Herons.

In 1975, after ending service to Paso Robles the year before, Hughes Airwest was operating McDonnell Douglas DC-9-30s to nearby Santa Maria Public Airport to serve the San Luis Obispo area; these nonstops to Los Angeles and San Francisco soon ended.

After the 1981 demise of Swift Aire after a merger with Golden Gate Airlines, Wings West Airlines established its headquarters in San Luis Obispo and flew several turboprop types, as an independent commuter carrier and then as American Eagle on behalf of American Airlines via a code sharing agreement. Propjets flown by Wings West to San Luis Obispo included the British Aerospace BAe Jetstream 31 and Jetstream 32, the Beechcraft C99, the Fairchild Swearingen Metroliner (Metro III models) and the Saab 340.

In 1987 the San Luis Obispo County Regional Airport was dedicated as McChesney Field, in honor of Leroy E. McChesney for his leadership and dedication to aviation. McChesney lived in the county since 1920 and had been a pilot since 1949. He was a longtime member of the California Aviation Council, a member of the California Aeronautics Board, and the Grand Marshal of the first Airport Day in 1984.

In 1988 a Federal Aviation Administration (FAA) control tower opened and SkyWest Airlines, WestAir operating as United Express and Wings West (later merged into American Eagle) were flying commuter turboprops, WestAir operating the Embraer EMB-110 Bandeirante and later the BAe Jetstream 31.

Several other commuter airlines served San Luis Obispo with turboprop flights to Los Angeles (LAX) including Delta Connection service by SkyWest with Fairchild Swearingen Metroliners (Metro II and Metro III models) and Embraer EMB-120 Brasilias, Imperial Airlines with Embraer EMB-110 Bandeirantes, Mesa Airlines flying as United Express with Beechcraft 1900Cs and USAir Express operated by Trans States Airlines with BAe Jetstream 32s. As of 1996 only American Eagle and United Express remained, Delta Connection and US Air Express having left the year prior.

America West Express (Mesa Airlines) began flying de Havilland Canada DHC-8 Dash 8s to Phoenix in April 1999. Within a few years they had expanded to Las Vegas, and became the first airline to operate regional jets to the airport with the Canadair CRJ-200. The Las Vegas route was dropped shortly after the US Airways/America West merger.

In 2007, Delta Connection (Skywest) returned to San Luis Obispo, flying a CRJ-200 to Salt Lake City. The route ended in 2008. American Eagle left the airport in November 2008 as they retired their Saab 340s as part of a 12% reduction in services, and closed its base at the airport.

On August 27, 2008, US Airways Express flown by Mesa Airlines announced an expansion of service at San Luis Obispo.