Munster centre Chris Farrell will win his first Ireland cap against Fiji on Saturday in a team which shows 13 personnel changes from that which beat South Africa 38-3 at Aviva Stadium.
Winger Darren Sweetnam, hooker Rob Herring and prop Andrew Porter all make their first starts, while Andrew Conway reverts to full-back.
Stuart McCloskey wins his second cap, having faced England in February 2016.
Joey Carbery and Kieran Marmion make up a new half-back partnership.
Leinster flanker Rhys Ruddock, a try-scoring replacement in the demolition of the Springboks last weekend, returns to the position of skipper which he held for the summer tour of the United States and Japan.
Conway scored the first try as Ireland recorded a victory in the first of their three autumn internationals but moves from the right wing to occupy the number 15 shirt.
Ulster centre McCloskey bridges a gap of almost two years since he played in the Six Nations against England at Twickenham, with Dave Kearney returning on the wing.
Sweetnam is rewarded for his fine form with Munster with a start after making his first appearance off the bench last week.
Carbery is handed a chance to impress at fly-half after ankle trouble denied the Leinster player the opportunity to face Japan in the summer, having been injured against the United States.
The 22-year-old made his debut in the famous win over New Zealand in Chicago 12 months ago and it appears Schmidt sees the versatile back’s future at international level more as a fly-half than at full-back or centre.
Connacht scrum-half Marmion replaced Conor Murray 10 minutes from the end of Saturday’s game and steps in to win his 18th cap, with Luke McGrath providing cover from the bench.
Loose-head Porter saw 29 minutes of action as a substitute against the US and 19 minutes against Japan, while Jack McGrath is back at tight-head after missing the encounter with South Africa to continue his recovery from a hip knock.
Herring steps out of the shadow of Ireland squad captain Rory Best to replace the British and Irish Lion, for whom he has regularly deputised at Ulster during international periods.
Dillane is joined in the second row by Devin Toner, who joins Conway as the only players to be retained from last week’s triumph over the two-time world champions.
Jordi Murphy and Jack Conan come in to join Ruddock in forming an all-Leinster back row.
Schmidt admits his experimental side face “a real challenge” against the Pacific Islanders and expects they will face “some really tough moments”.
“It will be interesting to see how they work through it. We want to give them a really stern test now to see if that progression can continue under real stress,” said the New Zealander.
“It’s always a concern making so many changes, but I can’t fault the application of this group. If they can bring that into the game, start well and get early confidence, I’d hope they can acquit themselves really well.
“There’s no better way to test people than to throw them into the arena,” said the New Zealander.
“The only problem with a Test is that you’re so visible, and any error is very visible, and you’re playing against players who will exploit any weakness.”
Ireland will complete their autumn international series against Argentina on 25 November, when a number of their first-choice players are expected to return.
Ireland XV: A Conway; D Sweetnam, C Farrell, S McCloskey, D Kearney; J Carbery, K Marmion; J McGrath, R Herring, A Porter, U Dillane, D Toner, R Ruddock (capt), J Murphy, J Conan.
J Tracy, C Healy, T Furlong, K Treadwell, CJ Stander, L McGrath, I Keatley, R Henshaw.