Although the Potters' first goal at Old Trafford in 30 years, Dean Whitehead's header from an unmarked position, had cancelled out Javier Hernandez's opener, Nani curled home a spectacular winner from 20 yards.
In October Hernandez had scored against Stoke with a jaw-dropping back header.
Last night's effort was no less audacious. Nipping in front of former United defender Ryan Shawcross at the near post, the Mexican striker reacted quickly as Nani drilled over a low cross.
Letting the ball run behind him, he quickly flicked back his right leg and turned it at right angles, to produce a goal-bound shot that Asmir Begovic thought he had covered.
It was Hernandez's ninth goal of the season and his second in four days.
Five minutes after the restart United were pegged back as Whitehead nipped between Nemanja Vidic and Patrice Evra to nod home Tuncay's cross unchallenged.
United look flustered for a while but when Danny Collins failed to get tight to Nani as he collected Hernandez's pass on the edge of the area, the Portugal winger turned swiftly before finding the bottom corner with a precise curling shot.
Victory opened up a lead of three points over Manchester City and five on Arsenal ahead of their meeting at the Emirates Stadium tonight.
Scott Dann snatched a dramatic 89th-minute winner for Birmingham at Blackpool as Alex McLeish's side moved away from the relegation zone with a 2-1 victory.
Dann met Roger Johnson's header across goal and took a touch before dispatching a cool half-volley past Richard Kingson.
Birmingham had led at half-time through Alexander Hleb's early solo goal, but DJ Campbell pegged them back with 22 minutes to go with a half-volley.
Fulham eased the pressure on under-fire manager Mark Hughes as they climbed out of the drop zone with a romping 3-0 win over West Brom.
A howling error from Baggies goalkeeper Scott Carson gifted them the lead as he failed to deal with Simon Davies's shot that was fired straight at him.
Davies then turned provider for goals two and three, which were virtually identical as Clint Dempsey and then Brede Hangeland headed in corners from close range. Birmingham and Fulham are now both two points clear of trouble, in 15th and 13th place respectively.