City's 21-match winning streak in all competitions was interrupted by a 2-0 defeat by Manchester United but normal service was quickly resumed at the Etihad Stadium as they opened up a 14-point gap at the top.
After a slow start City went ahead with their first attack when De Bruyne pounced to convert a rebound in 15th minute, only for James Ward-Prowse to equalise from the penalty spot. Mahrez restored City's lead and Ilkay Gundogan made it 3-1 in first-half stoppage time before Mahrez produced another clinical finish 10 minutes after the interval.
Che Adams replied for an adventurous Southampton but De Bruyne grabbed his second of the night shortly afterwards as City looked like scoring every time they attacked.Southampton, who played impressive football at times, have 33 points from 28 games and are only seven points above the relegation zone after a ninth defeat in 11 games.