Wolfsburg, who have found their form since sacking coach Felix Magath last month, also ended their opponents' seven-game unbeaten run.
Diego, who won the Europa League on loan at Atletico Madrid last season but was left on the bench by Magath, curled in a stunning 23-metre free-kick after four minutes and notched his third goal in three games from close range after a layoff from Dutchman Bas Dost.
Dost grabbed one for himself after the roles were reversed and Diego started the move with a delightful chip to charging Marcel Schaefer who cut the ball back for the forward to score.
Stefan Kiessling pulled one back in stoppage time for his seventh goal of the season.
"If you have to wait until Nov. 11 for your first home win of the season then you can imagine how we feel," said Wolfsburg interim coach Lorenz-Gunther Kostner.
"After Diego's 1-0 everything came pouring out. I am proud of the team for the way they played in the first half. We then stayed focused and made almost no mistakes in the second."
Wolfsburg's win lifted them to the relegation playoff spot with Leverkusen dropping to fifth on 18 points following their first league defeat since mid-September.
Leaders Bayern Munich, on 30, maintained a seven-point lead at the top with a 2-0 win over Eintracht Frankfurt on Saturday. Second-placed Schalke 04 beat Werder Bremen 2-1 to move up to 23 points.
ABDELLAOUE GOALS
In other action on Sunday, Europa League competitors Hannover 96 staged a spectacular comeback, recovering from 2-0 to crush hosts VfB Stuttgart 4-2 with Mohammed Abdellaoue scoring twice in five minutes in a thrilling game.
Christian Gentner and Vedad Ibisevic with a spot-kick gave the hosts a 2-0 lead at half-time before Artur Sobiech and Jan Schlaudraff, with another penalty, drew Hannover level.
Norwegian Abdellaoue tapped in from close range in the 69th minute and converted the third spot-kick of the game awarded for a foul on Lars Stindl to lift Hannover to 17 points in sixth place.
Borussia Monchengladbach were in similar battling mood, twice coming back from a goal down for a 4-2 win over Greuther Fuerth who had two players sent off.
The hosts led 1-0 thanks to a 10th-minute Bernd Nehrig penalty but two minutes later had Thomas Kleine sent off with a straight red for bringing down Patrick Herrmann outside the box.
It did not take long for Gladbach to make their advantage pay.
Hermann broke free on the right to cross for defender Oscar Wendt to head in but Fuerth went back in front with Edgar Prib before Gladbach struck twice in six minutes through Herrmann and Martin Stranzl.
Thorben Marx's 90th-minute penalty after Milorad Pekovic got his marching orders for a hand ball completed the comeback.
Gladbach move up to eighth on 16 points.
