Michael Carrick struck the all-important winner with just four minutes remaining, after Carlos Tevez had dragged United back on level terms.
The Latics had threatened the shock of the season as they led for the first hour thanks to Hugo Rodallega's first-half strike.
With just one point from their previous five games, they had turned the formbook upside down to give the champions elect the fright of their lives.
Then minutes after coming off the bench Tevez hit the equaliser and with four minutes left, Carrick hit the winner to leave United needing just one point to retain the title.
But it was heartbreaking for the Latics after a battling performance demanded by boss Steve Bruce.
The Latics had made just one change with Emmerson Boyce restored to the defence and Paul Scharner given a supporting role to lone striker Rodallega.
United made five changes with Paul Scholes, Wayne Rooney and Carrick among the returning stars, but Rio Ferdinand was again ruled out.
Both sides missed early chances and it was United target Antonio Valencia who almost gave Wigan a shock lead inside the opening two minutes.
The Ecuador winger raced clear but under pressure from Nemanja Vidic the finish was poor as hit it wide.
United then had two great chances within a couple of minutes with Rooney involved on both occasions.
Dimitar Berbatov got past Titus Bramble to fire in the cross but somehow the England star put the header wide from six yards.
Rooney responded by sparking another attack with a powerful break and this time Ronaldo set up the strike but Carrick was off target.
With the rain pouring down, Wigan threatened again with Edwin van der Sar keeping out a Charles N'Zogbia free-kick and then holding a left-footer from Rodallega.
But the Colombian striker was in dreamland as he hammered Wigan into a 28th minute lead.
Lee Cattermole banged in a deep cross and Rodallega reacted before Vidic to fire past van der Sar from six yards with the United midfielder claiming he was the victim of a push.
United, and Ronaldo in particular, were becoming increasingly frustrated by Wigan's no-nonsense approach, but Rooney should have done better when he was handed a great chance to level it just before half-time.
Then in stoppage time the Latics carved out another chance but Rodallega dragged the shot wide after a Valencia inspired attack.
United sent on Tevez and the Argentinian made an instant impact with the 61st minute equaliser.
Carrick supplied the ball into the box and Tevez cheekily back heeled it past Richard Kingson with the Red Devils' fans again urging Sir Alex Ferguson to give him a new contract.
Ronaldo had a penalty appeal turned down and blasted another chance wide, but Carrick made no mistake with the winner after John O'Shea set up the chance.