The New Zealand-born powerhouse, whose father Fe'ao represented Tonga and is a cousin on Wales star Toby Faletau, replaces Joe Marler.
Vunipola has made seven appearances from the bench and is one of five changes made by England coach Stuart Lancaster following victory over France.
Toby Flood replaces injured Owen Farrell at fly-half, Danny Care regains the number nine jersey from Ben Youngs in the backs.
Up front James Haskell returns to blindside flanker and Tom Youngs starts at hooker.
2009 Lions tourist Tom Croft is in the squad for the first time in 11 months following a serious neck injury but there is no place for Vunipola elder brother Billy.
Unbeaten England go into the game top of the Six Nations table, having won three games in a row.
They hold a 17-point advantage over nearest rivals Wales, whom they face in the final round of the championship in Cardiff next Saturday.
"We were very happy with the way we finished the France game," said England head coach Stuart Lancaster.
"The impact the replacements made shows that we have competition for places across the board and we have had to make some tight calls.
"Italy will be highly motivated for this game and we will have to perform for the full 80 minutes.
"I am sure those starting will seize their chance and the bench will also have a significant part to play as the game goes on."
Vunipola was delighted to be handed a first start but still hopes to be united with his brother while on England duty.
"It will be a great occasion for me and my family," added Vunipola.
The dream for us is to be out there together for my family. Hopefully one day that will happen."