Tom James will make his first Wales appearance since 2010 against Ireland on Sunday, while Rob Evans and Justin Tipuric will also start the Six Nations clash at the Aviva Stadium.
Cardiff Blues wing James joins Six Nations debutant Gareth Anscombe and George North in a new-look back three for the eagerly awaited encounter with the defending champions in Dublin.
Captain Sam Warburton lines up at blindside flanker, while Dan Lydiate has to settle for a place on the bench as Tipuric gets the nod at openside and Taulupe Faletau is handed the number eight shirt by Warren Gatland.
Evans gets his chance at loose-head at the expense of Gethin Jenkins, who is among the replacements, while Jonathan Davies returns from injury to feature alongside Jamie Roberts in a vastly experience centre pairing.
There is no place on the bench for full-back Liam Williams, who made his comeback from a foot injury for Scarlets last weekend, or Hallam Amos.
Gatland said: "We are excited by the make-up of the squad, it's very experienced along with one eye looking to the future,
"Rob [Evans] gets a start at loose-head, he's played well for us before and deserves a chance looking ahead to the next few years.
"We have been impressed with Tom James' form for Cardiff Blues and we are excited by the mix of the back-row which has played well together before.
"It's great to see Jonathan [Davies] back and alongside Jamie [Roberts], which makes a pretty experienced midfield. Gareth at full-back also gives us the option of having two first receivers.
"We have a very experienced bench, with a lot of caps there and hopefully they will come on and make an impact.
"It's going to be a physical game. Two years ago they strangled us out of the match and played well and we have to rise to that challenge on Sunday."
Wales: Gareth Anscombe, George North, Jonathan Davies, Jamie Roberts, Tom James, Dan Biggar, Gareth Davies; Rob Evans, Scott Baldwin, Samson Lee, Luke Charteris, Alun Wyn Jones, Sam Warburton, Justin Tipuric, Taulupe Faletau.
Replacements: Ken Owens, Gethin Jenkins, Tomas Francis, Bradley Davies, Dan Lydiate, Lloyd Williams, Rhys Priestland, Alex Cuthbert.