The league was initially to be contested by 60 teams, but was reduced to 59 following the exclusion of Trapani.
Following the disbandment of Sicula Leonzio and Siena, two relegated clubs were readmitted as members of Serie C. On 4 October 2020, Trapani was excluded from the league after failing to play two consecutive matches.
The winner of the play-offs earns promotion to Serie B.
The Triestina vs Virtus Verona game, originally scheduled to be played on 9 May 2021, was delayed due to eight cases of COVID-19 infection involving the latter club.
The draw for the first national round was held on 20 May 2021, 11:00 CEST (UTC+2).
The draw for the second national round was held on 27 May 2021, 11:00 CEST (UTC+2).
If teams are tied on aggregate, the winner is decided by extra-time and a penalty shootout if required.
The Fano vs Imolese game was postponed due to a cluster of confirmed COVID-19 cases involving the former team.