A total of 12 teams will contest the league, including 10 sides from the 2020–21 Guatemala Liga Nacional and 2 promoted from the 2020–21 Primera División.
Sacachispas and Sanarate were relegated to 2020–21 Primera División the previous season.
The relegated team were replaced by the 2020–21 Primera División winners Nueva Concepción and Sololá.
Relegated to Primera División de Ascenso as of August 2021.
Achuapa Antigua Cobán Imperial Comunicaciones Guastatoya Iztapa Malacateco Municipal Nueva Concepción Santa Lucía Sololá Xelajú