Chelsea's 7-1 thumping of Aston Villa had momentarily knocked the champions off top spot.
But Sir Alex Ferguson's side, chasing an historic fourth successive title, moved a point clear of Chelsea and four ahead of Arsenal with a convincing win.
Jlloyd Samuel gave the Red devils a helping hand when he put through his on net on 38 minutes - the 11th time an opposition player has scored for United this season.
And Berbatov, twice, and substitute Darron Gibson completed the rout.
The Bulgaria striker was leading the line in the absence of Wayne Rooney, who was left out completely to rest a niggling knee injury ahead of United's Champions League quarter-final with Bayern Munich in Germany on Tuesday night.
And he nearly opened the scoring but his instinctive volley was turned round the post by Jussi Jaaskelainen.
Johan Elmander was then denied by a superb stop by Edwin van der Sar after Jack Wilshere slipped him in with a delightful pass, before the visitors took the lead in most bizarre fashions.
Ryan Giggs' cross was just out of reach of Berbatov but Samuel, under no real pressure, drilled a low shot past a stunned Jaaskelainen.
Bolton would have been level immediately but for another world-class save from van der Sar.
Fabrice Muamba's shot was heading for the top corner when the Dutchman produced a miraculous save to tip over the midfielder's effort.
United were clearly rattled and a furious Ferguson charged onto the pitch to remonstrate with referee Martin Atkinson as the half-time whistle went.
The game opened up after the break but chances were at a premium until Jaaskelainen could only parry Darren Fletcher's drive and Berbatov pounced on 68 minutes.
Berbatov then flicked home Nani low cross on 78 minutes before Gibson added a fourth after more good work from the Portuguese winger.