Giacomo Raspadori and Tanguy Ndombele get their first start with Victor Osimhen as Napoli try to go joint top of the table, while Samuel Umtiti is on the Lecce bench.
It kicks off at the Stadio Diego Armando Maradona at 19.45 UK time (18.45 GMT).
The Partenopei lost their 100 per cent record with a 0-0 draw away to Fiorentina, but can still stay top alongside Roma with a victory here.
Luciano Spalletti rotates the squad with Raspadori, Ndombele, Leo Ostigard and Matias Olivera getting their first starts, Matteo Politano and Eljif Elmas also stepping in to rest Kvicha Kvaratskhelia and Hirving Lozano.
Lecce have Barcelona-owned defender Umtiti on the bench after his loan move.
The newly-promoted side picked up their first point with a 1-1 draw against Empoli, after very narrow defeats to Inter and Sassuolo.
Mert Cetin, Joel Voelkerling Persson and Kastriot Dermaku are still on the treatment table.
Napoli: Meret; Di Lorenzo, Ostigard, Min-jae, Olivera; Anguissa, Ndombele; Politano, Raspadori, Elmas; Osimhen
Lecce: Falcone; Gendrey, Baschirotti, Tuia, Pezzella; Helgason, Hjulmand, Askildsen; Banda, Colombo, Di Francesco