In medieval times, the town was the seat of the Lords of Mayenne.

The town originated when Juhel II of Mayenne (lord of Mayenne, Gorron and Ambrières (1110–1161)) built a monastery near the gate of the pre-existing castle, which led to the formation of the settlement.

Mayenne was besieged twice during the French Wars of Religion, in 1574 and 1590, and suffered substantial damage.

It was rebuilt and re-embellished in the following century thanks to the help of Cardinal Mazarin.

On 9 June 1944, during World War II, it was bombed by the RAF, which caused heavy damage and numerous casualties.