Ten teams contested the league: Albion Rovers, Annan Athletic, Cowdenbeath, Edinburgh City, Elgin City, Forfar Athletic, Kelty Hearts, Stenhousemuir, Stirling Albion and Stranraer.
The following teams changed division after the 2020–21 season.
The Pyramid play-off was contested between the champions of the 2021–22 Highland Football League (Fraserburgh) and the 2021–22 Lowland Football League (Bonnyrigg Rose Athletic).
The winners (Bonnyrigg Rose Athletic) then faced the bottom club in League Two (Cowdenbeath) in the play-off final.
As Bonnyrigg Rose Athletic won the final, they were promoted to League Two for the 2022–23 season and Cowdenbeath were relegated to the Lowland League.