The Bath star is omitted from the 24-man squad to continue preparations for the next phase of the Grand Slam defence, denying him even a bench role against Conor O'Shea's Azzurri.
It is the second time Joseph has been dropped by Eddie Jones, after making way for Elliot Daly in last autumn's victory over South Africa, and it is his rival from Wasps who could also usurp him at outside centre on this occasion.
Owen Farrell, who is set to win his 50th cap, will almost certainly start at fly-half inside a midfield partnership that may see Ben Te'o make his first start alongside Daly.
Te'o made a telling impact when coming off the bench against France and Wales, while Daly has been among England's best performing backs since breaking into the starting XV last autumn.
Anthony Watson is poised to appear in an England match-day squad for the first time since the June tour to Australia after recovering from the hamstring injury he suffered last month.
England, who will name their line-up on Friday, may give James Haskell his first start since the clean sweep of the Wallabies after declaring the openside is fit enough to step up from the 'finisher' role he has performed so far in the Six Nations.
England squad to face Italy: Forwards - J Clifford (Harlequins), D Cole (Leicester Tigers), J George (Saracens), D Hartley (Northampton Saints), J Haskell (Wasps), N Hughes (Wasps), M Itoje (Saracens), J Launchbury (Wasps), Courtney Lawes (Northampton Saints), Joe Marler (Harlequins), Kyle Sinckler (Harlequins), Mako Vunipola (Saracens), Tom Wood (Northampton Saints).
Backs - M Brown (Harlequins), D Care (Harlequins), E Daly (Wasps), O Farrell (Saracens), G Ford (Bath Rugby), J May (Gloucester Rugby), J Nowell (Exeter Chiefs), H Slade (Exeter Chiefs), B Te'o (Worcester Warriors), A Watson (Bath Rugby), B Youngs (Leicester Tigers).
