Kyle Walker, David Silva and Gabriel Jesus all find themselves on the bench to begin the Group F clash at the Stadio San Paolo in Naples.
With nine points and first in the group, City can lock up a spot in the knockout stage with a positive result. But with Arsenal looming on Sunday, Guardiola may be giving the trio a mid-week break with the club already well-positioned to advance.
Sergio Aguero is in the XI however, as the striker looks to secure his place in club history by moving into first all-time on their goalscoring charts.
The Argentina international needs just one goal to pass Eric Book, whom he is currently tied with on 177 tallies.
Also joining Aguero among the starters is Ilkay Gundogan, who makes his third start of the campaign for City.
Manchester City XI: Ederson; Danilo, Stones, Otamendi, Delph; Fernandinho (C), Gundogan, De Bruyne; Sane, Aguero, Sterling
Subtitutes: Bravo, Walker, Mangala, B. Silva, D. Silva, Jesus, Toure
Napoli XI: Reina, Albiol, Koulibaly, Hysaj, Ghoulam; Hamsik, Allan, Jorginho; Mertens, Callejon, Insigne
Subtitutes: Maggio, Zielinski, Chiriches, Sepe, Rog, Ounas, Diawara