Real Betis entered the tie in strong home form, having won their previous five matches in all competitions, and nearly made the perfect start when Abde Ezzalzouli curled an early effort narrowly wide. However, Atletico took control in the 12th minute when captain Koke swung in a corner that David Hancko powered home for his second goal of the season.
Deadline-day signing Ademola Lookman was heavily involved throughout. He missed an early one-on-one opportunity but soon made amends. Giuliano Simeone doubled Atletico's lead after finishing Matteo Ruggeri's cutback, before Lookman marked his debut with a goal eight minutes before half-time, cutting inside and finishing a swift counter-attack to make it 3-0.
Betis tried to respond after the break, but Juan Musso denied Ezzalzouli, and Atletico remained clinical. Just after the hour, Lookman turned provider, setting up Antoine Griezmann, who scored his fourth Copa del Rey goal of the season.
Substitute Thiago Almada added a late fifth after following up Griezmann's saved effort to secure a dominant victory.
Lookman, who joined from Atalanta during the January transfer window, expressed his delight after contributing a goal and an assist. He said: "Very proud, very happy for my debut, especially for the performance of the team.
"Everyone welcomed me in a very affectionate way. They made it easy for me."
He added: "I'll try to be regular this season. There are things that can be improved, but my intention is to continue working to improve."
The result marked Atletico's 11th win in their last 14 meetings with Betis and handed the hosts only their fourth home defeat of the season. Diego Simeone's side now prepare to face Betis again in La Liga on Sunday.
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