A seventh straight win for Massimiliano Allegri's side means they are now six points clear of second-place Napoli – a lead that could be reduced to five on Sunday should Sassuolo continue their fine start to the season by beating AC Milan.
Napoli took an early lead through Dries Mertens, before Cristiano Ronaldo and Mandzukic combined to equalise. The World Cup finalist scored again early in the second half after Ronaldo's shot had cannoned back off the post.
Mario Rui was dismissed in the 58th minute for the visitors before Leonardo Bonucci scored his first goal for the club since returning from Milan in August to seal the win 14 minutes from time.
After Pitor Zielinski hit the upright, Napoli broke the deadlock in the 10th minute by punishing Bonucci's sloppy pass with an incisive move that resulted in Mertens sliding Jose Callejon's cross into an unguarded net.
Juve drew level in the 26th minute when Ronaldo turned Elseid Hysaj inside out before whipping a fine cross into Mandzukic, who headed past David Ospina.
Ospina did brilliantly to push Ronaldo's 20-yard strike onto the post four minutes after the restart, but Mandzukic was on hand to slot the rebound home.
Napoli's hopes of finding a way back into the game were dealt a huge blow shortly before the hour mark when Mario Rui received a second yellow card for an ugly tackle on Paulo Dybala.
Bonucci prodded home Ronaldo's header off a corner at the back post to ensure Juve claimed yet another maximum haul, but the Portugal star spurned a great opportunity to make the scoreline more emphatic.
What it means: Forgiving Napoli have it all to do
Despite the scoreline, Juve were actually some way from their fluid best against last season's Serie A runners-up. The difference between the sides was a ruthlessness in front of goal, expertly demonstrated by consummate big-game player Mandzukic. Napoli have enjoyed a bright start to the season – winning five of their six games before this defeat – but already find themselves with a lot of ground to make up.
Mandzukic delivers again
Any thoughts the 32-year-old Croatian might not be as effective as he once was are being dispelled this season. Two more goals moved him onto four in the league – one more than his more heralded team-mate Ronaldo.
Mario Rui red mist proves costly
Napoli were still very much in the game when Mario Rui recklessly rolled his studs down Dybala's ankle, but his moment of madness all but ensured his side would leave empty handed.
Key Opta facts:
- This is first time Juve have won their opening eight games of the season since 1930-31.
- Ronaldo has delivered the most assists in Serie A this term (four).
- Mandzukic scored just his second Serie A brace and his first since December 2015.
- Two of Napoli's last three red cards in the league have gone to Mario Rui.