Relegation-threatened QPR saw manager Harry Redknapp resign on Tuesday, citing an imminent knee operation as the reason for his departure.
Chris Ramsey and Kevin Bond took caretaker charge of the Londoners on Saturday, and it looked as though they were set to oversee a hard-earned draw until Mane struck in the third minute of injury time.
QPR had stood firm for much of the match, despite the visitors dominating proceedings, and they even had chances to win it themselves before Mane struck.
But the Senegal man - back in the side after returning from the Africa Cup of Nations - proved his quality in the final moments.
The forward fired home a powerful strike into the roof of the net at the near post to break the home side's resistance and boost Southampton's aspirations of UEFA Champions League qualification.
Ronald Koeman's Southampton move up to third in the Premier League as a result, while QPR stay second bottom of the table with 19 points.
QPR named Adel Taarabt – a peripheral figure under Redknapp - in their starting XI as one of four changes aimed at increasing their threat in front of goal.
But it was Southampton who unsurprisingly dictated the early going, although without creating any clear-cut opportunities.
The visitors were dealt a blow in the 20th minute when Matty Targett suffered a head injury after being caught by a Matt Phillips elbow.
The left-back received treatment for several minutes before being taken off on a stretcher and replaced by Florin Gardos.
Despite that setback, Southampton continued to dominate proceedings and they would have taken the lead in the 34th minute had Jose Fonte's volley not cannoned off the crossbar after Mane had forced Robert Green to tip his shot around the post from close range.
Mane - by far the most dangerous player on the pitch - then got in behind the home defence again, only to fire wide of the far post.
Neither team could take advantage of the seven minutes of first-half stoppage time that came as a result of Targett's injury, and chances continued to be few and far between following the restart.
QPR gradually began to take control of the game, though, and only the heroics of Southampton goalkeeper Fraser Forster prevented them from going ahead.
The former Newcastle and Celtic shot-stopper pulled off a brilliant reaction save to keep out Charlie Austin's point-blank effort after Joey Barton's strike had deflected into his path.
Despite that near-miss, QPR would still have been content with a point against one the Premier League's form sides, but Mane snatched that away as he turned in the area and struck home the winner.
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