Rhys Webb is back for Wales at scrum-half against Italy in Rome on Saturday, his first Six Nations start since 2017.
The 34-year-old replaces Tomos Williams having last begun a Test three years ago, while Rio Dyer takes over on the wing from Louis Rees-Zammit.
Wales coach Warren Gatland also brings in Dafydd Jenkins, Jac Morgan, Liam Williams and prop Wyn Jones.
Lock Alun Wyn Jones, Christ Tshiunza, Leigh Halfpenny miss out while Gareth Thomas drops to the bench.
Dan Biggar has been ruled out by a back problem so Owen Williams continues at fly-half for winless Wales, with versatile Joe Hawkins providing stand-off cover while starting at centre.
Veteran Ospreys lock Jones is also out of the squad with his 22-year-old team-mate Rhys Davies on the bench to back up regional colleague Adam Beard and Exeter's Jenkins.
Tshiunza is another to miss out altogether with Leicester Tigers' Tommy Reffell the back row cover.
Ospreys prop Thomas drops to the bench, with George North, 30, also among the replacements as cover for Wales' 20-year-old centres Hawkins and Mason Grady.
Wales' back play has only produced one try in the tournament so far, with their other two scores coming from a driving maul and an interception.
So much will rely on the Ospreys trio of half-backs Webb and Owen Williams and Hawkins as the inside centre playmaker.
However Wales also have the worst discipline in the Six Nations.
Liam Williams is recalled despite yellow cards in both his previous appearances in the tournament but with a warning from Gatland ringing in his ears. Halfpenny, his replacement against England, is ruled out with a hamstring complaint.
With Italy also without a win, the trip to Rome is viewed by many as a wooden spoon decider with Wales going to Paris to face France a week later.
Gatland said: "We feel that having watched Italy and how they'll tend to play from everywhere, including their own 22, getting guys on the ball is going to be pretty important.
"Rhys Webb gets an opportunity at nine having been training well. He's been great in the squad, he brings that experience and a voice to that nine position.
"Liam Williams comes in at full-back. We did discuss whether we put Louis Rees-Zammit to full back and how that would have looked.
"But he still hasn't played a lot of rugby in terms of coming back from a relatively long injury with his ankle and we just felt with the way the game's going to be and the pace of the game, that him coming off the bench and the impact he can have could be pretty important.
"We've been disappointed with the results so far and for me it's hard to take as it's the first time I've lost three games in the Six Nations with Wales.
"We've had a lot of things going on off the field as well, but there are no excuses.
"The message to the players has been that we have to be smart in terms of the way we play, but we've also got to be brave and make sure that when the opportunities are on we shift the ball.
"We have to keep scanning and looking at options and if there's a chance to move the ball then be brave and do that."
Wales: Liam Williams; Josh Adams, Mason Grady, Joe Hawkins, Rio Dyer; Owen Williams, Rhys Webb; Wyn Jones, Ken Owens (capt), Tomas Francis, Dafydd Jenkins, Adam Beard, Jac Morgan, Justin Tipuric, Taulupe Faletau.
Replacements: Scott Baldwin, Gareth Thomas, Dillon Lewis, Rhys Davies, Tommy Reffell, Tomos Williams, George North, Louis Rees-Zammit.