The 2021–22 Serie D was the seventy-third season of the top level Italian non-professional football championship.
The nine playoff winners for each group will be prioritised to fill any potential Serie C league vacancies.
Two two-legged relegation playoff games (known in Italian as "play-out") will therefore be played between: In case of an aggregate draw after the second leg, two extra times will be played; in case of further aggregate draw, the worst-placed team will be relegated.
Five teams were directly relegated from the 2020–21 Serie C: Fano, Ravenna, Arezzo, Bisceglie, Cavese.
On 15 December 2021, debt-ridden FC Messina was excluded from the league with immediate effect due to having failed to show up for two consecutive league games; as the exclusion happened before mid-season, all previous games involving the club were voided.