Joining Nowell is full-back Ollie Devoto and scrum-half Callum Braley while props Scott Wilson and Danny Hobbs-Awoyemi, as well as flanker David Sisi, also get the nod.
"I missed the 20s campaign last season through injury so to have this opportunity is one that I'm really looking forward to," said Nowell.
"I played Italy at Under-18 level and they are in your face and physical, but this is a game that we're really looking forward to."
England are coming off the back of a scintillating 40-10 victory against France in Worcester, which followed on from victory in the opening game against Scotland and a narrow 16-15 loss to Ireland, but captain Jack Clifford is taking nothing for granted against the Azzurrini.
"This will be the third time I've played against Italy at this level and every time it's a physical battle," said Clifford, who scored a hat-trick against France.
"The Italians improve year on year and we're expecting an extremely tough match against them in Northampton. Fingers crossed we get a decent crowd down at the Gardens and it makes for a good atmosphere."