On a day where none of the top four sides played and Tottenham dropped points, United failed to take advantage, going down to an organised Stoke side at the Britannia Stadium.
In a first half largely dominated by United, Stoke went ahead after 38 minutes thanks to a deflected Charlie Adam free-kick.
The former Liverpool midfielder's effort hit Michael Carrick on the edge of the area, taking the ball beyond the reach of a helpless David de Gea.
United were level just two minutes after the break, Robin van Persie the man on target as he became the first player in Premier League history to score in eight successive appearances against a single opponent.
The visitors' celebrations were cut short however, when Adam unleashed an unstoppable effort past De Gea from outside the area after 52 minutes.
It proved to be the winner as United lost their eighth league game of the season and their third straight match on the road in all competitions.
Rooney then had the first chance of the game, turning and firing wide inside the area after 14 minutes following Patrice Evra's cross from the left.
From there, United began to pile on the pressure, Van Persie next to go close with an effort that deflected wide past Asmir Begovic's right-hand post.
However, seven minutes before the break, Adam's free-kick, with the help of a large slice of luck and an inadvertent Carrick deflection, put the home side ahead.
However, Van Persie was again the man to haunt Stoke as he angled a finish past Begovic following Mata's carefully-weighted throughball.
The scores were level for just five minutes however, when Adam registered his sixth league goal of the season with a magnificent left-footed strike.
But Stoke, who were in the relegation zone prior to kick-off, held on to move 11th in the table with their first league win since December.
