A controversial Samir Nasri goal and an Edin Dzeko header moments later turned a tight game in City's favour after Rickie Lambert's penalty had cancelled out one from Yaya Toure. Stevan Jovetic made victory certain, but for Southampton prime concerns were over a knee injury to 17-goal top scorer Jay Rodriguez.
Chelsea recovered from their recent malaise to return to the top of the league with a routine 3-0 victory over Stoke.
Making his full debut, Mohamed Salah netted the first. Frank Lampard followed up to score after Asmir Begovic saved his penalty and Willian curled in a third.
Fulham climbed off the foot of the table when Hugo Rodallega pounced for a late winner in a 2-1 victory at Aston Villa. With just four minutes remaining, Lewis Holtby floated in a cross that was met by Rodallega's glancing header.
Kieran Richardson had nudged Fulham into a 62nd minute lead with a super strike, only for Grant Holt to capitalise on poor defending to equalise.
Two goals from Jason Puncheon enabled Crystal Palace to take another giant stride towards Premier League survival by triumphing 3-0 at Cardiff.
Puncheon and Joe Ledley gave the Eagles a comfortable two-goal cushion, but Puncheon saved his best for last with an outstanding late strike.
West Brom secured a priceless 1-0 victory at Norwich when Morgan Amalfitano struck in the 17th minute.
George Boyd headed in a cross by Liam Rosenior at the far post as Hull dispatched Swansea 1-0.