The visitors arrived at the Rhein Neckar Arena looking to take advantage of Schalke's defeat to leaders Bayern Munich on Saturday and move up to fourth in the table.
Yet they were behind after just four minutes when reported Liverpool target Roberto Firmino struck with a perfectly weighted lob.
Wolfsburg restored parity just over 10 minutes later through Bas Dost's header, but the hosts struck back with a flurry of three goals in a six-minute spell towards the end of the first half.
First, Niklas Sule headed his side back in front after getting on the end of Sejad Salihovic' free-kick before Anthony Modeste stamped his authority on proceedings with a stunning brace to secure a 4-1 half-time lead for the home side.
Modeste opened his account with a well-struck low drive from the edge of the box, before beating his man to power home a header for his second goal.
Only Borussia Dortmund and Bayern have scored more goals in the league than Hoffenheim this season, but the hosts seemed to ease up in the second half.
That allowed Wolfsburg's Ivan Perisic to pull one back after turning in Kevin de Bruyne's cross, but any hope of a comeback was extinguished when Christian Trasch brought down Kevin Volland in the box and was sent off.
Salihovic stepped up to score from the resulting penalty, before playing through Sven Schipplock late on to add a sixth.
In the day's other game, Eintracht Frankfurt eased their relegation fears with a 2-1 win over fellow strugglers Stuttgart at the Commerzbank Arena.
Martin Harnik gave Stuttgart the lead just after the half-hour mark, after capitalising on some good work from Alexandru Maxim.
Maxim should have doubled the lead deep into the second half when he was presented with an empty net, but he somehow contrived to miss the target.
The visitors were made to pay for their wastefulness almost immediately, as Frankfurt went up the other end to take the lead through substitute Jan Rosenthal, who rounded off a terrific counter-attack with a cool finish.
And the win was wrapped up with just a minute to spare, when Johannes Flum managed to get the better of Georg Niedermeier, before squaring to Alexander Meier to score.
Frankfurt now sit six points ahead of Sunday's opponents, who are only out of the relegation zone on goal difference and remain in trouble.
