Aston Villa's club record signing Darren Bent made his mark with a debut goal for his new club in a 1-0 win that dented Manchester City's hopes.
Spain striker Fernando Torres reproduced his old clinical finishing, which has been largely missing this season, with two goals as a rejuvenated Liverpool beat Wolverhampton Wanderers 3-0 at Molineux.
That gave interim manager Kenny Dalglish, a lethal scorer in his day too, his first win in his second spell as Liverpool boss.
Berbatov's hat-trick - his third of the season - spearheaded unbeaten United to a 5-0 win over Birmingham City at Old Trafford while Van Persie's treble gave Arsenal a 3-0 triumph over Wigan Athletic at the Emirates Stadium where the Dutchman also missed a penalty.
United have 48 points from 22 games, two points ahead of Arsenal who have played one match more than the leaders.
Manchester City slipped from second to third on 45 points having played 24 games.
Bent, who joined Villa from Sunderland this week for 18 million pounds, found City's net after 18 minutes for the only goal of the game at Villa Park, pouncing on a poor flap from goalkeeper Joe Hart.
Champions Chelsea, who have 38 points from 22 matches, will get the chance to close the gap on the leading trio when they travel to Bolton Wanderers on Monday.
TWO MINUTES
It took Berbatov two minutes to find the net at Old Trafford, heading in from point-blank range as United took a grip of a game they never relinquished.
The Bulgarian, who has scored three against Liverpool and five against Blackburn Rovers this season, was on target again after 31 and 53 minutes to take his league tally to 17 goals.
Berbatov also played a part in Ryan Giggs's goal just before half-time. Nani added the fifth after 76 minutes.
"I was delighted we got a good start, that puts the other team under a lot of pressure. They have a plan and then they have to change it," United manager Sir Alex Ferguson told Sky Sports.
"We played very well, the passing was good and we produced a good performance today."
While Berbatov was banging in the goals in Manchester, Van Persie was doing the same in North London as Arsenal made it six wins out of six in home Premier League matches against Wigan.
Van Persie, who missed two months of the season through injury but is now returning to his best form, has scored six goals in his last three games but could have made that seven after blasting a penalty high over the Wigan bar.
Manager Arsene Wenger said Arsenal could have scored as many as 10 goals such was their command of the match. "But what is most important was the team performance, which was great," he added.
"We know we have eight home games left and it is important we win them. We are hungry and we want to do well."
