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 player with some great skills."
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 at a low ebb after fellow New Zealander Wayne Pivac, his successor, guided the national side to just three wins in a 2022 that also included shock home defeats by Italy and Georgia.
The Welsh Rugby Union (WRU) has also been beset by off-field problems over allegations of misogyny, sexism, racism and homophobia within the governing body that led to the resignation of chief executive Steve Phillips on Sunday.
Wales (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
Coach: Warren Gatland (NZL)
