Napoli are transformed with Simone Verdi, Adam Ounas and Vlad Chiriches starting against a very mobile Sassuolo 3-4-3.
It kicks off at the Mapei Stadium at 17.00 GMT.
The hosts have Andrea Consigli suspended, with Marlon injured, but Coach Roberto De Zerbi – a former Napoli striker – opts for a 3-4-3 formation with Domenico Berardi, Filip Djuricic and Jeremie Boga in attack.
Rogerio and Federico Peluso take the wide roles.
Napoli also have their goalkeeper sitting out a ban, as Alex Meret was sent off in last week’s controversial 2-1 defeat to Juventus, so David Ospina steps in.
Raul Albiol is injured, but Carlo Ancelotti rotates the squad ahead of Thursday’s Europa League second leg Round of 16 with RB Salzburg.
Arkadiusz Milik is among those rested, as Dries Mertens and Lorenzo Insigne are joined by Adam Ounas and Simone Verdi.
Sassuolo: Pegolo; Lirola, Demiral, Ferrari; Rogerio, Duncan, Magnanelli, Peluso; Berardi, Djuricic, Boga
Napoli: Ospina; Malcuit, Chiriches, Koulibaly, Ghoulam; Ounas, Diawara, Allan, Verdi; Mertens, Insigne