The striker claimed the points in the third minute of injury time after James McArthur had caught Wes Brown in possession to complete a miserable afternoon for the Black Cats.
Sebastian Larsson had put the home side ahead with just eight minutes gone, and Bruce's men would have been out of sight had it not been for Latics keeper Ali Al-Habsi.
However, Jordi Gomez's 44th-minute penalty gave Wigan hope, and a much-improved second-half display saw them clinch the win in a dramatic conclusion.
Sunderland have now won just two of the 15 league games they have played on Wearside since New Year's Day, and Bruce was left in little doubt as to the feelings of the supporters both before and after the final whistle.
Bruce had targeted a return of seven points from a run of four games which started with last week's home clash with Fulham and will continue with a trip to Wolves and Blackburn's visit to the north-east.
A single point from the first six on offer represents significantly less that he was expecting, and that is simply not acceptable for those fans who believe the manager is living on borrowed time.
For Wigan, a priceless victory to go with last week's draw with Blackburn after a run of eight defeats provided a welcome boost.
Former Latics boss Bruce went into the game with club chairman Ellis Short having delivered an endorsement of sorts by insisting in his programme notes that there was no need for panic.
For 43 minutes, the home supporters among a crowd of 37,883 must have been reassured that the Texan businessman's confidence was well-founded.
The Black Cats were utterly dominant as Wigan showed exactly why they are languishing at the foot of the table, creating nothing of note going forward and struggling to stem the tide at the back.
Had it not been for keeper Al-Habsi, they might have gone in at the break already beaten as Sunderland created chances at will.
Yet it was the Oman international's error which handed the home side an eighth-minute lead.
Nicklas Bendtner had been ordered by Bruce to be more selfish in front of goal, and his swerving right-foot shot proved too hot for Al-Habsi to handle.
The keeper spilled the ball and although he managed to block Kieran Richardson's follow-up, the ball ran to Larsson and he thumped it home left-footed to get the Black Cats off to the perfect start.
Thereafter, Wigan were indebted to their goalkeeper as Bruce's side threatened to kill the game off in double-quick time.
He produced a fine save low to his left to keep out Richardson's near-post drive and then blocked Brown's header on the line from the resulting corner.
Al-Habsi distinguished himself once again with 23 minutes gone to palm away Larsson's free-kick and then recover to claim Phil Bardsley's follow-up.
He then rescued his defence 12 minutes before the break when John O'Shea was allowed to get his head to another Larsson free-kick.
Wigan belatedly worked their way into the game, although Conor Sammon and Ronnie Stam were unable to take advantage of half-chances.
However, they were back on level terms by the time the whistle sound, although the equaliser arrived in controversial circumstances.
Not for the first time, Victor Moses forced his way into the penalty area from the left-hand side and went down under Larsson's challenge.
The Swede protested his innocence, but to little effect as referee Kevin Friend pointed to the spot with television replays proving inconclusive.
Gomez, however, took full advantage, sending Keiren Westwood the wrong way to hand his side a share of the spoils they scarcely deserved.
Stephane Sessegnon returned in determined mood and carved his way through the Wigan defence within seconds, although he could not pick out any of the three team-mates who had kept pace with him.
Bendtner screwed a 48th-minute shot wide in a lively start to the half which kept Mr Friend fully occupied.
He turned down penalty appeals from both sides in quick succession as first Jack Colback blasted a shot into James McCarthy's arm from point-blank range and Sammon went to ground after going shoulder-to-shoulder with Brown.
Gary Caldwell headed a 68th-minute Larsson free-kick just over his own crossbar, but the visitors were more than making a game of it as time ran down.
But the winner eventually arrived at the other end when, after McArthur had embarrassed Brown, he squared for Di Santo to apply the decisive touch.