Halfpenny, who has won 97 caps for his country, last featured in the starting line-up when Wales beat Canada in 2021.
He is joined in the back-three by Josh Adams and Rio Dyer, with Ospreys centre Joe Hawkins winning his second cap after being preferred to Saracens' Nick Tompkins.
Gatland selected a starting back row of Jac Morgan, Justin Tipuric and Taulupe Faletau. Veteran former skipper Alun Wyn Jones partners Adam Beard at lock, with Wales now led by Scarlets hooker Ken Owens.
"We've picked Joe (Hawkins) at 12," said Gatland in a statement issued after the team to play world number one-ranked Ireland was announced Tuesday. "He is a lovely footballer with some great skills."
"I thought for his first cap (against Australia last year) he was outstanding so we’ve given him another opportunity. There’s some real competition in the midfield at the moment, so I’m really excited about that.
"Ireland are the number one team in the world, so they’re going to be coming here with a lot of confidence. You don’t become the number one team in the world without having some pretty consistent performances."
Gatland's previous reign as Wales boss, from 2007 to 2019, yielded four Six Nations titles, three Grand Slams and two World Cup semi-finals.
But Wales are now at a low ebb after fellow New Zealander Wayne Pivac, Gatland's successor, guided the national side to just three wins in a 2022 that also included shock home defeats by Italy and Georgia.
Meanwhile, the Welsh Rugby Union has also been beset by allegations of misogyny, sexism, racism and homophobia within the governing body.
Claims of a "toxic culture" at the WRU were aired in a television documentary last week, resulting in the resignation of chief executive Steve Phillips on Sunday.
Ireland have had no such off-field drama and will arrive at the Principality Stadium as the world's number-one ranked side after a superb 2022 that included a series win in New Zealand.
Head coach Andy Farrell, who is due to announce his team on Thursday, will be aware, however, that Ireland have lost their last four Six Nations games in Cardiff.
Gatland, who coached Ireland from 1998-2001, added: "We know how good they are and we are expecting a really tough contest. It's important for us that we start well, but we need to be in the game at the last 20 minutes.
"We've only had a couple of weeks together, but I am confident the guys will go out and give a good account of themselves."
Wales lineup (15-1):
Leigh Halfpenny; Josh Adams, George North, Joe Hawkins, Rio Dyer; Dan Biggar, Tomos Williams; Taulupe Faletau, Justin Tipuric, Jac Morgan; Alun Wyn Jones, Adam Beard; Tomas Francis, Ken Owens (capt), Gareth Thomas
Replacements: Scott Baldwin, Rhys Carre, Dillon Lewis, Dafydd Jenkins, Tommy Reffell, Rhys Webb, Owen Williams, Alex Cuthbert
Follow the Six Nations opener between Wales and Ireland on Flashscore.
