Mills' Gloucester team mate, scrum half Dan Robson, is named amongst the replacements.
Newcastle Falcons No. 8 Alex Gray will skipper the side, while Aviva Premiership winner Owen Farrell starts as a replacement.
Harlequins lock Sam Twomey and London Irish wing Marland Yarde will both claim their first England U20 caps should they get on the pitch from the bench.
Leicester Tigers fly half George Ford, who will start at No.10, said that this game will be different to the 6 Nations clash played out in Athone a few months ago, but accepts that England need to concentrate on themselves.
"They were missing a few players last time we played them and they'll be back now," he said. "It's a different game, it's a different environment and different things are at stake.
"We've got to focus on ourselves and our own game, we'll give them the upmost respect but ultimately it's about us and how we play on the day."
Ford added: "This is the opening game and it doesn't get much tougher, but we want to start this competition as we mean to go on and that means playing well, doing all we can to get the win and taking it from there."
England U20 starting XV to play Ireland
1) Mako Vunipola (Saracens)
2) Mike Haywood (Northampton Saints)
3) Henry Thomas (Sale Sharks)
4) Joe Launchbury (London Wasps)
5) Charlie Matthews (Harlequins)
6) Matt Kvesic (Worcester Warriors)
7) Matt Everard (Leicester Tigers)
8) Alex Gray (capt) (Newcastle Falcons)
15) Ben Ransom (Saracens)
14) Andy Short (Worcester Warriors)
13) Elliot Daly (London Wasps)
12) Ryan Mills (Gloucester Rugby)
11) Jonathan Joseph (London Irish)
10) George Ford (Leicester Tigers)
9) Chris Cook (Bath Rugby)
16) Rob Buchanan (Harlequins)
17) Ryan Bower (Leicester Tigers)
18) Sam Twomey (Harlequins)
19) Sam Jones (London Wasps)
20) Dan Robson (Gloucester Rugby)
21) Owen Farrell (Saracens)
22) Marland Yarde (London Irish)
Content courtesy of RFU.