Mertens' superb finish, a powerful shot into the top corner from the edge of the box, made him Napoli's joint-top scorer of all time in Serie A with 102 league goals, alongside Antonio Vojak.
Lazio mustered a response as Ciro Immobile and Sergej Milinkovic-Savic scored in the space of three minutes, but any hopes of a comeback ended when Napoli substitute Victor Osimhen powered home his side's fifth in the 80th minute.
Lazio's five-match league winning run ended but they have a chance to make up ground when they face second-placed AC Milan, on 66 points, in Rome on Monday.
"On Monday we have another head-to-head. We have a bonus, the game in hand over the others, those are another three points up for grabs," said Lazio assistant coach Massimiliano Farris.
"We can't give up, after the incredible run we have made."
Referee Marco Di Bello judged that Milinkovic-Savic had illegally caught Kostas Manolas in the head as he cleared from a corner, and awarded a spot-kick that Insigne calmly converted.
Politano cut inside and drilled a shot home after 12 minutes, before Lazio striker Joaquin Correa's shot came back off the post.
Insigne lifted a shot over Reina from the edge of the area to begin a run of superb individual goals in the second half, followed by Mertens' unstoppable strike and a curling Immobile finish.
Milinkovic-Savic curled a free kick into the top corner before Osimhen blasted home.