Its name used to be "Rochester Municipal Airport", before adding customs and immigration facilities specifically for Mayo Clinic purposes in 1995.

Rochester was one of the first destinations from the Twin Cities in Northwest Airlines history, behind Chicago, Winnipeg, Green Bay, and Fargo.

During World War II, the Army Air Corps conducted training operations from the airport.

In 1960, it was decided to replace Lobb Field with a new airport southwest of town because it could not be expanded to allow larger airliners and was too close to the urban area of Rochester.

On December 4, 1970, Imperial Airways announced it was canceling its scheduled helicopter flights in Minnesota, including from Minneapolis–St Paul to Rochester.

[1] The Rochester International Airport was the site of the six-hour 2009 tarmac stranding incident that made international news and resulted in the first fines ever imposed on airline carriers by the United States Department of Transportation for stranding passengers on a tarmac.

[10] In July 2019, the Rochester Airport Commission began accepting bids for the jet bridge project.

The commission also discussed repaving parts of runway 02/20 as well as additional dining and shopping options in the terminal.

[11] At the end of July 2019, the airport received $3.3 million in federal grants to improvements, including the jet bridge project and runway reconstruction.

[12] In February 2020, the airport was awarded $750,000 by the United States Department of Transportation for attracting new service, with the federal grant's stated purpose being "revenue guarantee and marketing program to attract new service to Denver on United Airlines.

[18] On May 31, 2018, Elite Airways announced that they would be launching service direct to Phoenix, Arizona, and St. Augustine, Florida, starting in July 2018.

The airport is also home to the Southeastern Minnesota Flying Club, which has had a presence at both RST and its predecessor Lobb Field for over 50 years.