The 2021–22 season was U.S. Alessandria Calcio 1912's first season back in second division of the Italian football league, the Serie B, and the 110th as a football club.

Note: Flags indicate national team as defined under FIFA eligibility rules; some limited exceptions apply.

Note: Flags indicate national team as defined under FIFA eligibility rules; some limited exceptions apply.

Players may hold more than one non-FIFA nationality.

Win Draw Loss Fixtures Source: Soccerway Source: Serie B The league fixtures were announced on 24 July 2021.