The Red Devils lost their grip on top spot just 24 hours earlier after Liverpool's thrilling 4-4 draw with Arsenal, but goals from Wayne Rooney (9) and Michael Carrick (82) sent Sir Alex Ferguson's side back to the summit, with a game in hand on their north-west rivals.
United drew first blood when Anderson's delightful ball picked out Ryan Giggs and the veteran winger crossed for Rooney to tap past David James.
The Red Devils continued to press with Rooney again and then Anderson going close with shots. But Pompey had two escapes when first Nadhir Belhadj scrambled the ball off the line, while James repelled Giggs when the Welshman was played through on goal moments later. Giggs was again marginally off target when Cristiano Ronaldo slide the ball into him, while Rooney was denied a second by a linesman's flag after rounding James and slipping the ball home.
United continued to press after the interval with Rooney and Giggs once again going close, while Peter Crouch volleyed wide following a rare Pompey attack.
The champions kept probing for that elusive second and it finally arrived when Paul Scholes found Carrick in the 82nd minute and his low shot was drilled accurately into the bottom corner.
The victory lifts United three points clear of Liverpool at the top of the table, with the champions still boasting a match in hand. Pompey stay 14th, six points clear of the drop zone.
Down at Stamford Bridge, Everton showed Chelsea their cup final teeth but having the better of an entertaining goalless draw.
It was the Toffees who had the first chance when Jo found himself through on goal but he spurned the chance, while Didier Drogba (twice) and Florent Malouda both tried their luck for Chelsea.
But Everton soon came back with Steven Pienaar's drive flying just wide, Leighton Baines being denied a penalty after a trip in the area, and Tim Cahill's turn and shot testing Petr Cech.
But Jo was another glorious chance when he found himself through on goal, the Brazilian slipping as he shot with just Cech to beat.
And Everton started the second half well with Cahill's flying header testing Cech once again, while Tim Howard was at his best to push away John Terry's 30-yard left-footed drive.
Jo then lashed another chance wide, while Frank Lampard saw a shot blocked by brave defending as the match swung from end to end.
Howard then denied Salomon Kalou, Cahill's shot struck the sidenetting, while Pienaar blazed wide with the goal at his mercy.
The closest Chelsea came was in added-on time when Drogba's shot on the turn cannoned back off the crossbar with Howard beaten.
But it wasn't to be as the match fizzled out into a goalless draw, with the result probably spelling the end of Chelsea's distant title dreams. Everton, meanwhile, close to within a point of fifth-placed Aston Villa.