The other change sees Angelo Esposito replace Leonardo Sarto on the wing as O'Shea largely keeps faith with the side that lost 31-15 to Argentina last weekend.
"The last selection (of the year) is always the hardest to do for a coach," O'Shea said in a media release from the Italian Rugby Federation on Thursday.
"We wanted to keep the group that played this trio of matches, while at the same time adding a bit of freshness with the choice of Angelo and Giovanni from the first minute."
Loose-forward Renato Giammarioli has been added to the bench and will earn a first cap if he comes on, while South African-born Braam Steyn will start in the number seven jersey.
Italy stunned the Boks with a 20-18 victory in Florence in 2016, their first victory over South Africa.
But they have won only one of their 11 tests since then, a run that includes defeats to Tonga and Fiji.
With Georgia having moved above them in the World Rugby Rankings, there have been questions raised as to whether Italy still deserve their place in the Six Nations.
Another victory over the inconsistent Boks would strengthen their credentials.
Team:
15-Jayden Hayward, 14-Angelo Esposito, 13-Tommaso Boni, 12-Tomasso Castello, 11-Mattia Bellini, 10-Carlo Canna, 9-Marcello Violi, 8-Sergio Parisse (captain), 7-Abraham Steyn, 6-Giovanni Licata, 5-Dean Budd, 4-Marco Fuser, 3-Simone Ferrari, 2-Luca Bigi, 1-Andrea Lovotti.
Replacements: 16-Leonardo Ghiraldini, 17-Federico Zani, 18-Tiziano Pasquali, 19-Francesco Minto, 20-Renato Giammarioli, 21-Edoardo Gori, 22-Ian McKinley, 23-Matteo Minozzi.
(Reporting by Nick Said; Editing by Ken Ferris)
