Giacomo Raspadori leads the Napoli attack with Kvicha Kvaratskhelia, while Milan revamp the defence again and rely on Rafael Leao and Christian Pulisic.
It kicks off at the Stadio Diego Armando Maradona at 19.45 GMT.
These sides famously met four times last season between Serie A and the Champions League quarter-final, Napoli winning 2-1 at San Siro in controversial circumstances, then losing 4-0 at home to a Leao brace.
The European clash was won 2-1 by Milan on aggregate, with both teams seeing a penalty parried.
Victor Osimhen is still out after an injury on international duty, with Andre Frank Zambo Anguissa only fit for the bench, so Raspadori is again chosen ahead of Giovanni Simeone.
Milan welcome back Mike Maignan and Theo Hernandez from bans against Juventus, but Malick Thiaw is suspended with Ruben Loftus-Cheek, Samuel Chukwueze, Ismael Bennacer, Marco Sportiello and Mattia Caldara sidelined.
Pierre Kalulu steps into defence, as Simon Kjaer also has a muscular issue, with Rade Krunic preferred to Yacine Adli.
A result is badly needed for the Rossoneri after defeats to Juve and Paris Saint-Germain.
Napoli: Meret; Di Lorenzo, Rrhamani, Natan, Mario Rui; Elmas, Lobotka, Zielinski; Politano, Raspadori, Kvaratskhelia
Milan: Maignan; Calabria, Kalulu, Tomori, Theo Hernandez; Reijnders, Krunic, Musah; Pulisic, Giroud, Leao
Player statistic
| 22' |  |
Olivier Giroud (Assist: Christian Pulisic) | ||
| 31' | |
Olivier Giroud (Assist: Davide Calabria) |
| Matteo Politano (Assist: Giovanni Di Lorenzo) |
|
50' | ||
| Natan |  |
53' | ||
| 55' | |
Tijjani Reijnders | ||
| 62' | |
Luka Romero | ||
| Giacomo Raspadori | |
63' | ||
| Giovanni Di Lorenzo | |
65' | ||
| 78' | |
Yunus Musah | ||
| Alessandro Zanoli | |
86' | ||
| Natan |  |
89' |
Match statistic
