Gerry Taggart and James Scowcroft overcame injury doubts to start for City who also included former United defender John Curtis.
Paul Scholes was back for United after a month out with a hernia problem while midfielder Darren Fletcher was making his first Premiership start.
United threatened first when a quickly taken free kick by Scholes found Quinton Fortune in space on the left but after cutting inside he dragged his 18-yard shot wide of the goal.
The Foxes won the first corner of the game from which Scowcroft sent a glancing header wide.
United created another good chance on eight minutes when a Scholes free kick found Fletcher on the left. The Scottish international cut inside Ben Thatcher but then drove his shot straight at Ian Walker.
Paul Dickov took advantage of hesitancy in the United defence to chip the ball through to Marcus Bent who lifted a shot over the advancing Tim Howard, but the ball drifted just wide of the goal.
The visitors then stunned the Foxes with two goals in as many minutes.
With 15 minutes gone, a clever Scholes chip picked out Roy Keane who got in front of the keeper to score from close range.
City had no time to recover before a long-range effort by Scholes fell to van Nistelrooy who swivelled to fire home from ten yards.
United almost made it three when a Ryan Giggs cross from the left was side-footed just wide by van Nistelrooy.
Taggart climbed high at the far post to get on the end of a Muzzy Izzet free kick but his powerful header was comfortably saved by the well-placed United keeper.
Five minutes before the break, City threatened again with Scowcroft heading an Izzet cross over the bar.
A minute before half time, United cruised into a three-goal lead when van Nistelrooy got on the end of a long pass from Rio Ferdinand and went past Frank Sinclair before smashing a shot into the roof of the net from six yards.
With an eye on the midweek Champions League tie with Stuttgart, Sir Alex Ferguson withdrew Keane at half time and sent on Eric Djemba-Djemba.
Nistelrooy completed his hat-trick on 51 minutes when he latched onto Djemba-Djemba's throughball and guided a 16-yard shot inside Walker's far post.
On the hour mark, City went close when Howard did well to beat out Jordan Stewart's close-range drive and then Paul O'Shea reacted quickly to block Bent's follow-up effort.
On 64 minutes Walker limped off with a bad back to be replaced by Danny Coyne.
The Foxes gave their fans something to cheer on 74 minutes when Sinclair got above a static United defence to head home an Izzet corner.
It was Leicester's first goal against United in their last seven Premiership encounters.
Bent almost pulled another goal back for Leicester when he smacked a 25-yard angled drive against the crossbar.
Leicester: Walker (Coyne 64), Curtis, Sinclair, Taggart (Stewart 57), Thatcher (Rogers 40), Nalis, Izzet, Scimeca, Scowcroft, Bent, Dickov.
Subs Not Used: Howey, Impey.
Man Utd: Howard, Gary Neville, Ferdinand, O'Shea, Phil Neville, Fletcher, Keane (Djemba-Djemba 45), Scholes (Forlan 56), Fortune, van Nistelrooy, Giggs (Butt 61).
Subs Not Used: Ronaldo, Carroll.
Attendance: 32,044
Referee: G Poll (Hertfordshire).