Francesco Calzona is looking for his first Napoli win with Victor Osimhen and Kvicha Kvaratskhelia, but Sassuolo debut under interim coach Emiliano Bigica.
It kicks off at the Mapei Stadium at 17.00 GMT.
These Serie A Week 21 fixtures were postponed from January due to the Supercoppa Italiana in Saudi Arabia.
The Partenopei have all but given up on a Champions League spot and risk not even qualifying for Europe after a disastrous post-Scudetto campaign.
Calzona is their third coach of the season and has so far overseen 1-1 draws against Barcelona in the Champions League and Cagliari in Serie A.
Giovanni Di Lorenzo returns after suspension, but Jens Cajuste is added to the absentee list with Cyril Ngonge, so Hamed Junior Traore starts.
Matteo Politano is brought back into the trident attack with Osimhen and Kvaratskhelia, sending Giacomo Raspadori to the bench.
Sassuolo sacked Alessio Dionisi on Sunday after a run of one win and one draw in 13 games between Serie A and the Coppa Italia.
The 3-2 home defeat to Empoli was the final straw, leaving them hovering just above the relegation zone, so youth team coach Bigica was promoted as a temporary solution.
It is probably no coincidence that the worst period of form also saw Domenico Berardi out injured and he is back on the bench today, along with not fully fit Martin Erlic.
Jeremy Toljan and suspended Daniel Boloca miss out.
Birthday boy Nedim Bajrami, Kristian Thorstvedt and Armand Laurienté support Andrea Pinamonti.
Sassuolo: Consigli; Pedersen, Ruan Tressoldi, Ferrari, Doig; Racic, Matheus Henrique; Bajrami, Thorstvedt, Laurienté; Pinamonti
Napoli: Meret; Di Lorenzo, Ostigard, Rrahmani, Mario Rui; Anguissa, Lobotka, Traore; Politano, Osimhen, Kvaratskhelia
Player statistic
| Uros Racic |  |
17' | ||
| 29' | |
Amir Rrahmani (Assist: Frank Anguissa) | ||
| 31' | |
Victor Osimhen (Assist: Matteo Politano) | ||
| 41' | |
Victor Osimhen (Assist: Matteo Politano) |
| 47' | |
Victor Osimhen (Assist: Khvicha Kvaratskhelia) | ||
| 51' | |
Khvicha Kvaratskhelia (Assist: Victor Osimhen) | ||
| 75' | |
Khvicha Kvaratskhelia |
Match statistic
