The 2021 División Intermedia season, named "Cincuentenario del Club Atlético 3 de Febrero y Homenaje al Lic.
[3] General Caballero (JLM) won their first División Intermedia title with four matches to spare, following a 4–1 victory over Rubio Ñu on 27 September 2021.
Pastoreo F.C., who were entitled to enter this year's competition as 2019–20 Campeonato Nacional de Interligas champions, had their debut postponed to 2022 per decision by the APF's Executive Committee, since Guaraní de Trinidad already held the berth reserved to the Unión del Fútbol del Interior (UFI) for this season.
[6] Source: APF The fourth-placed team in the División Intermedia, Sportivo Ameliano, played a double-legged promotion play-off against Sportivo Luqueño, the ninth-placed team of the relegation table of the 2021 Primera División season.
Sportivo Ameliano won 4–3 on aggregate and were promoted to Primera División.