National head coach Eddie Jones pairs Ford and Youngs at half-back, with Tigers prop Ellis Genge named among the finishers.
Mako Vunipola is back from injury at loosehead prop, with Kyle Sinckler and Luke Cowan-Dickie also returning to the starting front row.
Team captain Owen Farrell moves to centre alongside Henry Slade.
Jones said: “We’re pleased to have Mako and Kyle back into the team and we’ve made some changes to our starting XV, but our finishers are just as important to our game plan. We look at the whole 80 minutes.”
England versus Italy is live on ITV 1 and BBC Radio 5 Live Sports Extra. Kick-off is at 2.15pm on Saturday.
15 Elliot Daly (Saracens, 48 caps)
14 Anthony Watson (Bath Rugby, 47 caps)
13 Henry Slade (Exeter Chiefs, 35 caps)
12 Owen Farrell (C) (Saracens, 89 caps)
11 Jonny May (Gloucester Rugby, 62 caps)
10 George Ford (Leicester Tigers, 73 caps)
9 Ben Youngs (Leicester Tigers, 105 caps)
1 Mako Vunipola (Saracens, 63 caps)
2 Luke Cowan-Dickie (Exeter Chiefs, 27 caps)
3 Kyle Sinckler (Bristol Bears, 40 caps)
4 Maro Itoje (Saracens, 44 caps)
5 Jonny Hill (Exeter Chiefs, 5 caps)
6 Courtney Lawes (Northampton Saints, 86 caps)
7 Tom Curry (Sale Sharks, 29 caps)
8 Billy Vunipola (Saracens, 57 caps)
16 Jamie George (Saracens, 55 caps)
17 Ellis Genge (Leicester Tigers, 24 caps)
18 Will Stuart (Bath Rugby, 9 caps)
19 Charlie Ewels (Bath Rugby, 17 caps)
20 Ben Earl (Bristol Bears, 9 caps)
21 Jack Willis (Wasps, 2 caps)
22 Dan Robson (Wasps, 8 caps)
23 Max Malins (Bristol Bears, 4 caps)