Leinster’s two-time Champions Cup-winning stalwart, who boasts Ireland’s highest number of replacement appearances with 58 caps from the bench, will earn just his 10th Test start this weekend.
Ireland skipper Best has been rested, along with the likes of Robbie Henshaw, as Schmidt’s men take on Italy at the Stadio Olimpico on Sunday.
Cronin will start, while Munster hooker Niall Scannell is among the replacements.
Asked if this is Cronin’s big chance to put the squeeze on Ireland skipper Best, head coach Schmidt replied: “I’m sure that’s his intention, as much as he’s very team-orientated. He will personally want to put his best foot forward.
“And to be fair to Niall Scannell he will want to do the same thing. Because two years ago he was picked on the bench, Rory got ill the day before the game and Niall Scannell came in.
“And that was really his big step on to the stage. He played superbly in that game two years ago. He’s just been in and out since because of various injuries.
“But both those hookers, it’s really interesting for us to have a look at.
“At the same time they are up against the centurion hard man of the Italian front-row in Leonardo Ghiraldini, and that’s a super challenge for them as well.
“I’m sure Sean Cronin’s excited. He’s trained well, hopefully that gives him the confidence to step out and do a really good job.
“He will have the confidence he brings from the 10 starts, but also the amount of game time he has had over the years.
“It’s a great opportunity for Sean and one I’m hopeful he’ll grab with both hands.
“We actually named him to start the third Test in Australia, but then he picked up a hamstring strain which was a real shame.
“It’s not like he doesn’t know we’ve got faith in him.”
Regular captain Rory Best will miss just his second Six Nations match in the last 63, a run dating back to 2007.
Peter O’Mahony will skipper the side from the back-row, with Jordi Murphy featuring at number eight rather than on the flank.
Ireland will field the exact same backline that started the 22-13 win in Scotland on February 9, with Conor Murray and Johnny Sexton piloting the side at half-back.
Connacht fly-half Jack Carty could make his Test debut off the bench, with Joey Carbery sidelined.
“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.”
Ireland’s starting XV: D Kilcoyne (Munster), S Cronin, T Furlong (both Leinster), U Dillane, Q Roux (both Connacht), P O’Mahony (Munster, capt), S O’Brien (Leinster), J Murphy (Ulster), C Murray (Munster), J Sexton (Leinster), J Stockdale (Ulster), B Aki (Connacht), C Farrell, K Earls (both Munster), R Kearney (Leinster).
Replacements: N Scannell (Munster), J McGrath (Leinster), John Ryan (Munster), I Henderson (Ulster), J Van Der Flier (Leinster), J Cooney (Ulster), J Carty (Connacht), A Conway (Munster).
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