Goals from Gonzalo Higuain, Manolo Gabbiadini and Marek Hamsik, who scored twice, put the Italian side firmly in control of their quarter-final, and gave Benitez plenty to celebrate on his 55th birthday.
Higuain broke the deadlock with a contentious strike after 15 minutes, before turning provider for Hamsik to double Napoli's advantage in the first half.
Hamsik then added a second just after the hour following calamitous defending from Josuha Guilavogui, with substitute Gabbiadini adding a fourth with 13 minutes to play.
Nicklas Bendtner pulled one back for the Bundesliga side late on, but they face an uphill struggle to make the semi-finals when they travel to Naples on April 23.
A positive start from the hosts saw Kevin De Bruyne and Bas Dost cause problems, with the latter denied by Faouzi Ghoulam's crucial interception after 10 minutes.
Despite their early pressure, Wolfsburg found themselves behind five minutes later - albeit in controversial circumstances.
A diagonal pass from Dries Mertens was brought down by Higuain, seemingly with the aid of his arm, and the striker profited with a neat finish into the top-left corner.
The Argentina international was again influential midway through the opening half, taking a pass from Christian Maggio 30 yards from goal before delivering a sensational pass behind the Wolfsburg defence for Hamsik to stroke home.
Wolfsburg managed to regain some of their composure before the break, and went agonisingly close to halving the deficit when Andre Schurrle's drive was tipped onto the crossbar by Mariano Andujar in stoppage time.
Higuain should have extended Napoli's lead three minutes after the break having been spun away from two defenders, but Diego Benaglio made a superb stop having raced off his line.
A third was not too far away, though, with Guilavogui guilty of handing a goal to the visitors.
Jose Callejon anticipated an under-hit pass and raced onto the loose ball. He then delivered a low cross for Hamsik and the Slovakia international made no mistake from seven yards.
Substitute Ivan Perisic attempted to get the hosts back into the game as he found room 35 yards out, but his ambitious drive was wide of goal.
While Wolfsburg were wasteful, Napoli were thoroughly efficient and they added a fourth after 77 minutes as Gabbiadini drifted away from two defenders to head Lorenzo Insigne's cross under Benaglio's foot.
There was time for a late consolation for Dieter Hecking's side as Bendnter tapped home after excellent work by Perisic, giving Wolfsburg a glimmer of hope.
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