Sean Cronin will make his full Six Nations debut aged 32 and in his 68th cap when Ireland face Italy in Rome on Sunday.
Leinster's two-time Champions Cup-winning hooker already boasts Ireland's highest number of replacement appearances with 58 caps from the bench, and will earn just his 10th Test start this weekend.
Connacht fly-half Jack Carty could make his Test debut off the bench, with Joey Carbery nursing a suspected hamstring problem.
Regular captain Rory Best will miss just his second Six Nations match in the last 63, in a remarkable run dating back to 2007.
"Joey Carbery has a hamstring strain and wouldn't really have been available," said Ireland boss Schmidt. "It would have been too great a risk for him to feature.
"We probably would have started Johnny (Sexton) anyway to be honest. He's had one game and 23 minutes since the Munster game. He's had very little game time.
"And Joey has had a lot of game time and played the bulk of the game in Edinburgh."
Peter O'Mahony will skipper the side from the back-row, with Jordi Murphy featuring at number eight rather than on the flank.
Head coach Joe Schmidt has made just four changes from the line-up that edged past Scotland 22-13 on Saturday, February 9.
Ireland will field the exact same backline that started against the Scots, with Conor Murray and Johnny Sexton piloting the side at half-back.
— Irish Rugby (@IrishRugby) February 22, 2019
Ireland team to play Italy
Forwards: 1 Dave Kilcoyne (Munster), 2 Sean Cronin (Leinster), 3 Tadhg Furlong (Leinster), 4 Ultan Dillane (Connacht), 5 Quinn Roux (Connacht), 6 Peter O'Mahony (CAPTAIN, Munster), 7 Sean O'Brien (Leinster), 8 Jordi Murphy (Ulster)
Backs: 9 Conor Murray (Munster), 10 Jonathan Sexton (Leinster), 11 Jacob Stockdale (Ulster), 12 Bundee Aki (Connacht), 13 Chris Farrell (Munster), 14 Keith Earls (Munster), 15 Rob Kearney (Leinster)
Replacements: 16 Niall Scannell (Munster), 17 Jack McGrath (Leinster), 18 John Ryan (Munster), 19 Iain Henderson (Ulster), 20 Josh van der Flier (Leinster), 21 John Cooney (Ulster), 22 Jack Carty (Connacht)*, 23 Andrew Conway (Munster)
* Denotes uncapped player