Watch: Sterling double takes Man City top once more
The English champions move a point ahead of Liverpool, who host Chelsea at Anfield later on, with five games remaining for both sides.
Captain Vincent Kompany, Benjamin Mendy, De Bruyne and Leroy Sane returned among four changes and City quickly settled into total control of the game.
Sterling should have opened the scoring on 11 minutes when after a patient build-up, David Silva got to the by-line and picked out the England international who somehow sliced wide with an open goal at his mercy from close range.
After a similar sitter at Burnley last season, Guardiola quickly hooked Sterling in his frustration.
However, Sterling showed his maturity and why he is a contender for player of the year awards by redeeming himself in emphatic fashion just four minutes later.
A rare Palace foray forward left them exposed at the back and De Bruyne's sensational through ball allowed Sterling to break clear before side-footing the ball high beyond Vicente Guaita.
Palace inflicted City's only home league defeat of the season with a shock 3-2...