For the first time in 17 years, Barca are not involved in the knockout stages of the Champions League and had work to do in Italy after a 1-1 draw at the Camp Nou last week.
Xavi's men raced into a two-goal lead inside 13 minutes as Adama Traore's powerful run teed up Jordi Alba to open the scoring before Frenkie De Jong curled home from the edge of the area.
Lorenzo Insigne's penalty reduced Napoli's deficit, but Barca restored their two-goal cushion when Gerrard Pique found the far corner from Alba's cross.
Pierre-Emerick Aubameyang scored a hat-trick at Valencia on Sunday in just his fourth appearance for the club and showed his finishing prowess once more with a brilliant strike into the top corner on the hour mark as Traore grabbed another assist.
Matteo Politano pulled another goal back three minutes from time, but it was too little, too late for the Italians as they can now concentrate on winning a first Serie A title since 1990.