Roberto Firmino put the hosts in front after four minutes, but Bas Dost levelled out of the blue 10 minutes later.
Anthony Modeste then took charge of matters with two goals in the space of three minutes after Niklas Sule had headed Hoffenheim back in front.
Ivan Perisic pulled a goal back for Wolfsburg in the 76th minute, but a Sejad Salihovic penalty after Christian Trasch was sent off, and a Sven Schipplock goal completed the scoring to take Hoffenheim 10 points clear of the bottom three.
Hoffenheim looked keen to take revenge for a 3-2 defeat to Wolfsburg in the quarter-finals of the DFB-Pokal and Modeste's cross was turned over Diego Benaglio by Firmino after only four minutes.
Wolfsburg levelled at the end of their first attack of the game, Perisic's cross headed into the far corner from close range by Dost.
However, Hoffenheim were always the dominant side and Sule rose to meet Salihovic's free-kick to restore their advantage in the 37th minute.
Modeste then stuck twice in quick succession, first picking his spot in the bottom corner from the edge of the area before beating Benaglio from closer in after being left alone following a corner.
Hoffenheim took their foot off the pedal in the second half and Modeste was withdrawn, earning a standing ovation.
Coach Markus Gisdol may have been worried that was the wrong decision when Perisic turned in Kevin De Bruyne's cross to give Wolfsburg hope with 15 minutes left.
However, a foul by Trasch on Kevin Volland inside the penalty area gave Salihovic the chance to make if five from the penalty spot, and he took it before putting Schipplock through to make it six late on.