Juventus have to completely transform amid an injury crisis, but cling to Manuel Locatelli, while Victor Osimhen returns and Andre-Frank Anguissa makes his Napoli debut.
It kicks off at the Stadio Diego Armando Maradona at 17.00 UK time (16.00 GMT).
The timing of this Scudetto showdown could not have been worse for Max Allegri, as after one point from the opening two rounds against Udinese and Empoli, he also lost numerous players during the break for international duty.
Federico Chiesa picked up an injury for Italy, while South Americans Paulo Dybala, Alex Sandro, Juan Cuadrado, Danilo and Rodrigo Bentancur didn’t get back in time to play.
Arthur and Kaio Jorge are also injured, so Mattia De Sciglio and Luca Pellegrini are thrown into the starting XI for a 4-3-3 formation.
Moise Kean scored twice for Italy in a 5-0 win over Lithuania on Wednesday, but Dejan Kulusevski and Federico Bernardeschi are preferred in support of Alvaro Morata.
Napoli have some issues too, above all in midfield, where Diego Demme, Piotr Zielinski, Stanislav Lobotka, Dries Mertens and Faouzi Ghoulam are all carrying injuries.
It means ex-Fulham man Anguissa is thrown in for his debut from the start with Fabian Ruiz returning from his lay-off.
Osimhen saw his two-match ban for a reaction foul halved on appeal, so is available with Lorenzo Insigne.
Alex Meret is out for several weeks with a back injury and David Ospina rushed back from Colombia in time to start in goal.
Napoli: Ospina; Di Lorenzo, Manolas, Koulibaly, Mario Rui; Fabian Ruiz, Anguissa; Politano, Elmas, Insigne; Osimhen
Juventus: Szczesny; De Sciglio, Bonucci, Chiellini, Pellegrini; McKennie, Locatelli, Rabiot; Bernardeschi, Morata, Kulusevski