Three goals in eight minutes after the break from Thomas Lemar, Nikola Kalinic and Angel Correa helped Diego Simeone’s side coast to victory against the fourth-tier Catalan side in the round of 32 second leg at the Wanda Metropolitano.
Elhadji Bandeh hit the post in the first half for the visitors and Antonio Adan produced an impressive save to keep out the Sant Andreu striker's header from close range.
However, Lemar's fine long-range effort sent Atletico ahead after 48 minutes, Kalinic headed home and Correa soon fired in a third.
Vitolo added a fourth with nine minutes remaining to complete a comfortable victory for Atletico.
Elsewhere, Girona came from behind to beat Deportivo Alaves 2-1 (4-3 on aggregate) and Barcelona host Cultural Leonesa later on Wednesday with a 1-0 first-leg advantage.
(Reporting by Rik Sharma, editing by Ed Osmond)
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