Joe Schmidt: 'If you want to learn, what better environment than a really white-hot atmosphere on Saturday?'
Prop Andrew Porter, 22, and lock James Ryan, 21, will be tasked with cementing the tighthead side of Ireland's scrum - with just nine caps between them ahead of Saturday's NatWest 6 Nations clash.
Pack mainstays Furlong and Henderson both miss out through hamstring problems, while Munster centre Chris Farrell will win just his third cap in replacing Henshaw, sidelined with shoulder trouble.
Head coach Schmidt accepted Ireland will definitely miss their injured "world-class" Lions trio - but insisted their replacements can thrive in the Test arena.
"There are always question marks. I know Rory Best, with over 100 caps, still asks himself questions before he plays," said Schmidt, when asked if he had questions over promoted trio Porter, Ryan and Farrell.
"You're always questioning yourself, there are always going to be scenarios that come up that you'd like to think you'd be prepared for, but you don't know how you're going to cope.
"So for a player who hasn't been there before, yes, it's a bit more pressure.
"The unknown is always a fear for pretty much any human being, and there is a little bit about the unknown going into this weekend."
On injured key men Furlong, Henderson and Henshaw, Schmidt continued: "They are world-class players, you don't suddenly replace world-class players, but we're a lot more focused on who we do have.
"Who we do have is Andrew Porter, who is a really promising young player that we're excited about, and James Ryan likewise.
"I've been talking to Chris Farrell for three of four years, he's been a long-term project, and I thought he did really well against Argentina in only his second Test.
"We're short on experience and we're up against a team welcoming back three Lions (Dan Biggar, Leigh Halfpenny and Liam Williams) while we see three disappear.
"So yes that's not ideal, but at the same time, if you want to learn, what better environment than a really white-hot atmosphere in the Aviva on Saturday?"
Ireland will seek to defend their unbeaten Six Nations record in Dublin under boss Schmidt dating back to 2014 when facing Warren Gatland's Wales at the Aviva Stadium.
While the vastly experienced Devin Toner slots in for the injured Henderson, rookie lock Ryan will face his biggest Test-match battle yet.
The same is to be said for front-rower Porter and centre Farrell, both making their full Six Nations debuts.
Schmidt maintains, however, that he expects both Furlong and Henderson to be fit in time to face Scotland in Dublin on March 10.
"Iain was the closer of the two; Iain could probably have played on Saturday," said Schmidt, comparing Henderson's injury profile with that of Furlong. "But Iain wasn't able to complete training (on Thursday) so we're not going to risk him.
"Iain was very close, he could definitely play next weekend, and the week after he will be fine.
"Tadhg was close as well. We thought on Tuesday with Tadhg he may well make it, but the progress just stalled a little bit."
Who is your sportstar of the year?
Vote in the Irish Independent Sport Star Awards and you could win the ultimate sports prize.
Prizes include, tickets to Ireland's against Scotland in the Six Nations, All Ireland football and hurling final tickets and much more.