The hosts were already labouring badly when Jonny Evans was sent off for a reckless second-half challenge on Stuart Holden.
But United made light of the handicap and after Matthew Taylor had failed to take a glorious chance for the visitors, Berbatov pounced, netting his 21st goal of the season after the normally reliable Jussi Jaaskelainen had failed to hold Nani's long-range effort.
After missing each other on Tuesday, Rio Ferdinand and Fabio Capello were both present in the Old Trafford directors' box amid heightened speculation that John Terry is about to be reinstalled as England skipper.
Someone who looked suspiciously like Shakhtar Donetsk midfielder Douglas Costa was there too, an interesting development given United were so heavily linked with the Brazilian last year.
The major figure though was Sir Alex Ferguson, who began a five-match touchline ban by communicating with the home dug-out by telephone.
It was probably just as well Ferguson was in the sanctuary of the stands as his opinion of Andre Marriner's decision not to award United an early penalty when Javier Hernandez's shot bounced onto Gary Cahill's arm was probably not worth repeating.
Once that call went their way, Bolton enjoyed themselves.
Fabrice Muamba revelled in the space afforded to him by a United midfield too light on physical contact and with Kevin Davies and Johan Elmander getting the better of Evans and Chris Smalling the hosts creaked badly.
Edwin van der Sar got his positioning just right to ensure Martin Petrov's curling free-kick did not find the net, Daniel Sturridge failed to make the most of a half-chance and Elmander fired a thunderbolt straight at Patrice Evra.
There was over half an hour on the clock when the hosts carved out a decent chance, Antonio Valencia, on his first start since September, rolled a pass to Wayne Rooney.
The England man cut a cross back to Hernandez at the near-post but the Mexican could not keep his near-post effort on target.
Rooney was off target with a couple of efforts too but United were so lacklustre it was no surprise both Fabio and, more importantly, Dimitar Berbatov were introduced at the break.
The double change triggered a shift in momentum, with United gaining the initiative.
However, Berbatov's relative lack of pace compared to Hernandez was a major factor in the Bulgarian getting caught offside as he tried to gain half a yard in his attempts to reach through balls from Smalling and Rooney.
Petrov was not too far away with a speculative effort from an acute angle after he received the ball straight back from his own corner, proof that Bolton remained a huge danger.
The Red Devils were starting to force their opponents back though, even if the end product was more of an increase in pressure than anything tangible in the way of clear-cut opportunities.
Bolton survived when Rooney used his strength to collect a short pass from Ryan Giggs and lay the ball off to Berbatov.
The £30.75million striker managed to get his snap-shot away but it was marginally off target.
Cahill then outsprinted Berbatov to reach Valencia's through ball before the entire complexion of the contest changed with Evans' dismissal.
The Northern Ireland defender has never been regarded as a dirty player and on first glance, it appeared Evans had merely come out on top in a 50-50 duel for possession.
Marriner was close enough to come up with a different theory, producing a red card that forced Michael Carrick to take up a defensive position and Rooney to operate in central midfield.
For Holden, the injury was serious enough to warrant immediate calls for a stretcher, just over 12 months after he broke a leg in a tackle with Nigel de Jong that nearly forced him to miss the World Cup.
The loss of a player did not affect United's attitude as Wayne Rooney went close.
But there were gaping holes at the other end and Taylor could only hold his head in his hands as he sent a free header from eight yards straight at Van der Sar.
Bolton must have known such opportunities could not be squandered, even against a side with 10 men.
And as Berbatov tapped home, following Jaaskelainen's blunder, the feeling of this being a key day in the title battle was inescapable.