The original highway through Windsor, Poquonock and Suffield was created in the mid 1920s. State Highway 110 ran along parts of today's routes 159 and 75. Starting in Hartford, it followed Main Street north to Windsor Center; Poquonock Avenue into Windsor Locks and Suffield; and then Mapleton Avenue, northeast and then north across the state line.

When state roads were renumbered in 1932, SH 110 was split up among US 5A (today's Route 159), and Route 75, which included today's route from Windsor to Suffield, and the Mapleton Avenue route back to US 5A. Route 75 began and ended at US 5A, for a length of 13.35 miles. The portion later to become part of Route 75 – North Street in Suffield – was designated SR 901.

In July 1950, Route 75 was relocated from Mapleton Avenue to North Street, and extended into Massachusetts. SR 901 was replaced; the Mapleton Avenue segment became SR 902. In 1951, SR 902 was turned over to the town.

Impacts from Bradley International Airport

Originally called Bradley Field, the Windsor Locks airport opened for military use in 1941. In June 1942, Route 75 was closed to thru traffic, from Halfway House Road to the Suffield town line, for the duration of World War II. In 1947, the airfield began serving civilian flights as Bradley International Airport.

Around 1961, the state proposed widening 2.24 miles Route 75 to four lanes, from the new Route 20 freeway to the Suffield town line. This area is a mix of industrial and airport-related businesses, and has substantial traffic. This widening was completed around 1982.

Scenic Road

In January 2001, a segment from Austin Street in Suffield to the Massachusetts border was submitted to the Connecticut Scenic Road Advisory Committee. In March 2001, the committee determined that Route 75 near Austin Street did not meet the criteria, but approved the segment north of Stony Bridge Brook.