Rafael Benitez's side travelled to Sardinia hoping to close the gap on second-placed Roma and champions Juventus ahead of their respective games Sunday against Catania and Atalanta.
However Cagliari, beaten at home only once this season, produced a determined performance at a virtually empty Sant'Elia stadium to leave Napoli third but now two points behind Roma and seven behind Juventus.
Benitez's woes deepened when Reina, who made his return from recent injury for Napoli's final league game of the year, hobbled off on the stroke of half-time with an apparently fresh muscle injury.
Cagliari started in positive fashion and Nene had the ball in the net after five minutes only to be ruled offside -- earning a yellow card in the process after failing to heed the referee's whistle.
Four minutes later, however, the Sardinians were celebrating after a finely-worked move involving Radja Nainggolan and Davide Astori saw Nene drive the latter's delivery past Reina from ten yards out.
Goran Pandev was pulled down from behind by Astori and after the referee pointed to the spot Higuain stepped up and beat Vlada Avramov in the hosts' net.
Reina, meanwhile, was replaced by Rafael Cabral after pulling up and holding the back of his leg while collecting the ball under no pressure.
Pandev was then on the receiving end of a similar cross from Higuain but the Macedonian failed to connect while unmarked at the back post.
Napoli's frustration grew and Benitez replaced Insigne with Belgian midfielder Dries Mertens with 20 minutes remaining.
Two minutes later the visitors were in an uproar after a stunning volley by Spaniard Jose Callejon beat Avramov from distance but was chalked off after Pandev was ruled offside.
Ten minutes later Mauricio Pinilla rose above French defender Anthony Reveillere to send a header wide of Rafael's upright at the back post.
Earlier, Udinese had Thomas Heurtaux's 65th minute strike to thank for a 2-1 win away to struggling Livorno after Luca Siligardi had levelled for the hosts following Nicolas Lopez's opener on ten minutes.