Jose Mourinho had already played his trump card, bringing on Paul Pogba, who was only fit enough for the bench, and United stumbled to a shock home defeat despite Romelu Lukaku sparking a grandstand finish.
Asked what has to change now to get United into the top-eight teams in Europe, Mourinho retorted: "Everything".
During his spells with Porto, Chelsea, Inter and Real Madrid, Mourinho has developed a reputation as the master of stifling the opposition before striking at the most opportune moment, but the tables were turned in dramatic fashion here. "We tried, we lost and that's football".
Ben Yedder put Sevilla in front two minutes later when he blasted into the bottom corner before heading in a second shortly after. The United manager attempted to retrieve the situation by throwing on Anthony Martial and Mata, but it was too little, too late.
"We had good periods, we didn't have great control over the game, but I can't say there was anything wrong with my players and their intention to play", he said.
"The second goal made it impossible". Had David Moyes uttered such comments during his brief reign as United manager, he would have been lambasted, but even Moyes was able to take United into the Champions League quarterfinals. It would be naïve to think that they will not fight in this game.
United finally worked a clear opening in the 38th minute, a powerful drive from Marouane Fellaini beaten away by Sergio Rico after Alexis Sanchez turned a one-two into the path of the Belgium global, who was making his first start of 2018.
Mourinho's gamble on Fellaini appeared to have largely backfired as he failed to impose his physical presence on Sevilla's ball players in midfield. However, the Belgian's effort was saved by Sergio Rico at the near post.
The start of the second half saw Eric Bailly produce some last ditch heroics to keep United level, as Sarabia found Correa unmarked inside the United area, but the Ivorian's perfectly timed challenge prevented the striker from getting a shot away.
Ever Banega's corner was flicked on for Ben Yedder to get away a header that De Gea tipped on to the bar, only for it to agonisingly curl over the line.