In a hugely significant day at the bottom of the table, West Ham escaped from the relegation zone with a 2-0 win over doomed bottom-club Sunderland and Birmingham moved to the brink of safety thanks to a stoppage time winner over West Brom.
At the top of the table, a total of 67,706 spectators squeezed into Manchester United's Theatre of Dreams to witness the home side leap-frog Arsenal at the top of the table with a 3-0 win over Fulham.
Most of them went home happy to have witnessed van Nistelrooy's second goal, a stunning solo run from inside his own half finished in trademark clinical fashion.
The win lifted United to the top of the Premiership for the first time this season.
Arsenal can restore their lead with victory over Everton on Sunday but after defeat by Blackburn last weekend and their Champions League exit in midweek, there is no doubt the pressure on the champions is building up.
Newcastle maintained their drive to force their way back into the final reckoning by moving to within two points of Arsenal with a 5-1 win over Blackburn that did not reflect a battling display by the visitors.
Blackburn's efforts were rewarded when Damien Duff cancelled out Nolberto Solano's first half opener for the home side. But a free-kick from French winger Laurent Robert just after the hour mark gave Newcastle the edge and they ultimately ran out comfortable winners thanks to a Jermaine Jenas drive, an own goal by Vratislav Gresko and Craig Bellamy, all in the closing minutes.
Chelsea bolstered their grip on fourth place - the final qualifying spot for the Champions League - with a 5-0 win over Manchester City at Stamford Bridge.
Goals from Jimmy Floyd Hasselbaink - his first in four games - John Terry, Mario Stanic, Frank Lampard and William Gallas guided the Blues to a comfortable victory and gave their goal difference a boost that could prove immensely significant given how tight the race for fourth place is.
City's misery was compounded when Chinese international defender Sun Jihai was red carded near the end for his second bookable offence.
In a day of high drama at the other end of the table, Geoff Horsfield was Birmingham's hero with a header four minutes into injury time to lift Steve Bruce's side to within one victory of their manager's 38-point survival target.
The defeat and West Ham's win means West Brom are now nine points away from safety - a gap that looks too big with only seven games to play.
West Ham finally provided some proof of the mantra that they are too good to go down by outclassing Sunderland 2-0 at Upton Park.
Goals from Jermain Defoe and Freddie Kanoute vindicated manager Glenn Roeder's decision to leave Paulo di Canio out of his squad.
In the day's other games, Charlton went ahead against Middlesbrough through Finnish striker Jonatan Johansson but Malcolm Christie scored to earn the home side a share of the points.
James Beattie became the Premiership's top scorer with his 20th league goal of the season for Southampton, five minutes before the break to become the first Saints player since Matt Le Tissier in 1994 to break that barrier.
But it was Kevin Davies who was the Saints hero with a last minute equaliser after Villa had led 2-0 through Lee Hendrie and Darius Vassell.