Ogenyi Onazi’s late strike was too little too late to halt Napoli from gaining all three points, courtesy of a Gonzalo Higuain first ever hat-trick.
Bosnia and Herzegovina forward Senad Lulic placed Edoardo Reja’s men in the lead but Dries Mertens equalized for the hosts on 42 minutes with a wonder goal.
Lazio lost control when Albanian defender Lorik Cana saw red shortly after the break.
Argentine striker Higuain placed the Stadio San Paolo outfit in the lead in the 49th minute and doubled it seven minutes after the hour mark.
Onazi pulled one back for the Biancocelesti in the 82nd minute, but Higuain claimed the match ball with an injury time goal.
The loss means Lazio, who have earned 48 points from 33 games, now trails fifth-placed Inter Milan by five points and faces a stern battle for a place in Europe next season.
Napoli currently occupies the last Champions League slot in the table with 67 points.