On 2 October 2020, CONMEBOL's Council approved the implementation of format changes to the Copa Sudamericana starting from this edition, aimed at ensuring that each of the countries is better represented in the different stages of the competition.

The schedule of the competition will be as follows:[9][23] The draw for the first stage was held on 5 February 2021, 12:00 PYST (UTC−3), at the CONMEBOL Convention Centre in Luque, Paraguay.

The draw for the group stage was held on 9 April 2021, 12:00 PYT (UTC−4), at the CONMEBOL Convention Centre in Luque, Paraguay.

Teams from the same association could not be drawn into the same group, excluding the four losers of the Copa Libertadores third stage, which were seeded in Pot 4 and whose identity was not known at the time of the draw, and could be drawn into the same group with another team from the same association.

The draw for the round of 16 was held on 1 June 2021, 12:00 PYT (UTC−4), at the CONMEBOL Convention Centre in Luque, Paraguay.

If still tied, extra time will not be played, and a penalty shoot-out would be used to determine the winner (Regulations Article 2.4.2).