The former Real Madrid attacker put the visitors ahead and the hotly-tipped Colombian then ensured Andre Ayew's late strike for Elie Baup's men was a consolation only
Napoli kept their hopes of qualification for the Champions League knock-out stages alive with a 2-1 win at Olympique de Marseille on Tuesday.
The Italian side headed into the game looking to bounce back from their 2-0 defeat to Arsenal in the previous round of Group F.
Marseille were without a point following losses against the Gunners and Borussia Dortmund, and their hopes of progression were dealt a further blow as Napoli cruised to a comfortable victory.
Former Real Madrid winger Jose Callejon and Colombian attacker Duvan Zapata put Napoli in command, before Andre Ayew pulled one back for Marseille to set up a tense finish.
Napoli sit joint top of the group on six points with Arsenal and Dortmund following the German side's 2-1 win at the Emirates Stadium, but Marseille are well adrift at the bottom with nothing to show for their efforts.
Dimitri Payet returned for Marseille after serving a domestic suspension at the weekend, while defender Souleymane Diawara and midfielder Benoit Cheyrou also came in to the side.
The inclusion of striker Gonzalo Higuain was one of four changes made by Napoli coach Rafa Benitez, who also restored winger Dries Mertens to the starting XI in place of Lorenzo Insigne following Friday's Serie A defeat to Roma.
Marseille keeper Steve Mandanda was tested early when he was forced into a fine diving save to prevent winger Mertens from finding the net with a free kick after just two minutes.
However, Napoli controlled much of the early stages and, although midfielder Cheyrou went close for Marseille, they should have taken the lead in the 13th minute when defender Pablo Armero fired wide from close range.
The hosts frustrated Benitez’s side for long periods, but they were almost caught out on the counter-attack only for Higuain to inexplicably fire wide with only Mandanda to beat.
But, three minutes before the break, Napoli did deservedly go ahead as Callejon displayed great control to bring down Higuain's wonderful ball over the top before cutting inside Rod Fanni and firing a half-volley beyond Mandanda.
Marseille made a quick start to the second half and nearly drew level seven minutes after the break, only for Payet to head over the bar.
Elie Baup's side dictated the play for large periods as they looked to try to craft an equaliser, but their lack of quality in front of goal was summed up when Ayew failed to connect with a right-wing cross from Payet.
And their hopes were all but ended after 66 minutes when substitute Zapata curled a glorious right-footed effort into the top corner after latching on to a deft flick-on from Mertens.
Marseille laboured to try to find a way back into the game in the closing stages and, although Ayew found the net with a superb low volley four minutes from time, the 1992-93 European champions could not complete a late comeback and now face an uphill struggle to avoid finishing bottom of the group.