The 2021–22 SFA South Region Challenge Cup was the 15th edition of the annual knockout cup competition for senior non-league clubs in the central and southern regions of Scotland. The tournament entry increased from 142 to a record 161 teams thanks to additional clubs joining the East of Scotland Football League and West of Scotland Football League. The defending champions were Dunipace, who beat Broomhill 3–1 in the delayed final of the 2019–20 edition on 15 August 2021. However they went out of the competition in the second round, losing 2–1 to Sauchie Juniors.