Julian Brandt gave the Werkself the lead and goals from Javier Hernandez and Vladlen Yurchenko secured a deserved win for Roger Schmidt's men, who move up to fourth ahead of the weekend's fixtures.
Defeat leaves Wolfsburg seven points behind their hosts, and potentially nine points adrift of the top four heading into the final six games of the season.
Leverkusen were quick to assert their authority on the game with Karim Bellarabi looking lively down the left.
Brandt was also looking keen and after Max Kruse had the first shot of the evening blocked at one end, the 19-year-old Leverkusen attacking midfielder launched a fruitful attack at the other.
He played a neat one-two with Hakan Calhanoglu with the return pass timed to perfection and leaving Brandt with the sole task of deciding where to place his shot, picking his spot low to the left of Diego Benaglio.
Buoyed by his fifth goal of the season, Brandt exuded confidence as he tested Benaglio once again with Leverkusen keen to increase their advantage.
Calhanoglu went close to doing that early in the second half with a curling effort which just missed Benaglio's left-hand upright.
Leverkusen appeared to be in total control when Andre Ramalho gave away possession cheaply near his own goal, and with Bernd Leno also off his line, Josuha Guilavogui took aim from distance as the ball fell for him.
By the time the ball reached the goal, however, Leno was back in position and clutched the shot to his chest.
Robin Knoche was next to make a mistake, leaving substitute Hernandez with only Benaglio to beat, but the goalkeeper kept the shot out with his foot.
Karim Bellarabi then crossed for Hernandez, whose control let him down just a few yards from goal.
Hernandez accepted his next invitation to curl in an effort from just outside the corner of the penalty area, and he then supplied the pass that teed up Yurchenko for his first Bundesliga goal late on.