Only captain Siya Kolisi, prop Boan Venter, wing Kurt-Lee Arendse and fullback Damian Willemse will start from the team that defeated France 32-17 in Paris last time out as coach Rassie Erasmus offers opportunities to others.
Handre Pollard will play his first game on tour from flyhalf, with Morne van den Berg in the number nine jersey and a centre pairing of Ethan Hooker and Canan Moodie.
Wing Edwill van der Merwe makes up a back three alongside Arendse and Willemse.
Hooker Johan Grobbelaar will have props Venter and Zachary Porthen either side of him, with Jean Kleyn and Franco Mostert the starting locks.
Kolisi is at the back of the scrum with Ben-Jason Dixon and number eight Marco van Staden.
Erasmus has selected what looks like a 6-2 split between forwards and backs on the bench, though hybrid player Esterhuizen can come on as a flanker or centre.
With no specialist hooker backup, Van Staden will fill that void in yet another experiment from Erasmus.
"Marco played hooker for us at the (2023) World Cup, and he has been training in the position since, so it doesn’t make a difference whether he starts at loose forward and moves to hooker," Erasmus said.
"We said from the outset of the tour that we want to give as many players as possible a chance to play, and we believe this team is best suited to the threats Italy will pose.
"One of our key pillars is to build squad depth, and it’s great to have players like Jean, Handre, Edwill, and Ben-Jason back.
"Handre and Jean have played in Rugby World Cups, while Ben-Jason and Edwill have both performed for us at the highest level, and we are excited to see what they’ll bring this weekend."
South Africa hosted Italy for two tests in July and won 42-24 and 45-0.
South Africa team:
15-Damian Willemse, 14-Edwill van der Merwe, 13-Canan Moodie, 12-Ethan Hooker, 11-Kurt-Lee Arendse, 10-Handre Pollard, 9-Morne van den Berg, 8-Marco van Staden, 7-Ben-Jason Dixon, 6-Siya Kolisi (c), 5-Franco Mostert, 4-Jean Kleyn, 3-Zachary Porthen, 2-Johan Grobbelaar, 1-Boan Venter
Replacements: 16-Gerhard Steenekamp, 17-Wilco Louw, 18-RG Snyman, 19-Ruan Nortje, 20-Andre Esterhuizen, 21-Kwagga Smith, 22-Grant Williams, 23-Manie Libbok.
