Lautaro Martinez and Christian Eriksen dropped to the bench as Stefan De Vrij returned from injury following Saturday's win over Genoa out at the Marassi.
Inter grabbed the lead after Cristiano Biraghi's cutback from the left found an unmarked Danilo D'ambrosio, who sent a fine finish past Napoli shot-stopper Alex Meret eleven minutes gone.
The side from Naples almost hit back just before the 20-minute mark when Lorenzo Insigne deflected Piotr Zielinski's rasping shot from the area narrowly past the far corner.
Zielinski gave the Nerazzurri another scare shortly before the half-hour mark with a left-footed first-time effort bringing Inter's shot-stopper Samir Handanovic to a reactive palm.
Handanovic was given further work after getting down to thwart Matteo Politano getting one over his former club from the left-inside channel right on the half-hour mark.
Inter soon regrouped and almost had a second in stoppage time, but Meret stretched low to turn Marcelo Brozovic's first-time attempt behind for a corner-kick.
Romelu Lukaku, who netted a brace over the weekend, was finally given a look in two minutes from halftime but the Belgian headed straight at Meret following a cross from the right.
The first changes of the encounter arrived on the side of Inter just after 60 minutes, with Alexis Sanchez making way for Martinez while Antonio Candreva made way for Diego Godin.
Inter made the game safe shortly before the final 15 minutes when Martinez received a pass outside the area and opened up space to curl into the far corner off a right-footed shot.
More goals seemed in the offing as the Nerazzurri managed to break at will but Antonio Conte's charges weren't decisive, with the encounter ending 2-0 to overtake Atalanta, who they face this weeked.