The result extends the visitors' winless run to five matches across all competitions and intensifies pressure on head coach Michael Carrick.
Atletico struck almost immediately, with Alex Baena exploiting space behind Diogo Dalot inside the first minute before cutting the ball across for Pablo Barrios to side-foot home. Ayden Heaven's desperate attempt to clear only sent it over the line.
United responded with greater intensity, with Bryan Mbeumo testing Jan Oblak and Carlos Baleba forcing a save from the Atletico keeper.
The hosts remained dangerous and Alejandro Grimaldo struck the woodwork with a free-kick, before Johnny Cardoso had a goal disallowed near half-time for a handball by Marcos Llorente in the build-up.
Bruno Fernandes came closest for United, curling a shot off the crossbar around the 70th minute.
The turning point arrived in the 74th minute when Leny Yoro was shown a straight red card after a VAR review for denying Jonathan David a goalscoring opportunity as the last defender.
Five minutes later, Atletico made the numerical advantage count with the rebound from David's saved shot falling to substitute Ademola Lookman, who reacted quickly to convert and make it 2-0.
Lisandro Martinez has questioned Manchester United's transfer strategy and called on the club's hierarchy to take responsibility for the team's struggles following their 2-0 Champions League defeat to Atletico Madrid on Tuesday.
PSG coach Luis Enrique believes Manchester City should retain the trophies they won during the period covered by their Premier League financial breaches case, although he acknowledged that the final decision rests with the authorities.
Arsenal recorded a 3-0 victory over Lille in their Champions League clash on Tuesday night with all three goals coming in the second half.
German giants Bayern Munich were held to a 3-3 draw with Norway's Viking FK in their Champions League clash on Tuesday night.
