Forward Brianna Hoy will return home to Australia for surgery after rupturing her anterior cruciate ligament at training on Tuesday.
Star flanker Piper Duck (ankle) was also ruled out for the tour, while Tania Naden is unavailable due to a hand injury.
Wallaroos coach Jo Yapp has named Western Force duo Alapeta Ngauamo and Lucy Dinnen and former Melbourne Rebels forward Tiarah Minns on the bench for their international debuts.
It caps a remarkable rise for 31-year-old Dinnen, who has been part of the Wallaroos' training squads for close to a decade while also spending nine years in the army.
"One of my big goals in life was to wear this green and gold," Dinnen said.
"It's been 10 years since my first Wallaroos' camp, when I was 21.
"I've been chipping at it for quite a while. My hard work and perseverance has finally pushed through."
Your 23 to take on Ireland 🫡— Wallaroos (@WallaroosRugby) Catch it all on @StanSportAu 📺#Wallaroos pic.twitter.com/k4fcEUPCp1September 12, 2024
Minns has overcome a spate of injuries in her young career to make her Wallaroos debut, while Ngauamo's maiden Test appearance comes at age 36.
"With the props, the older you get, the better you get, they say," Yapp said of Ngauamo.
"She brings a really good attitude and she's super willing to learn even at the age she is."
Despite captain Michaela Leonard being named in the starting line-up, Siokapesi Palu will skipper the side against Ireland to build on the team's leadership depth.
Prop Bridie O'Gorman starts in Hoy's absence, Leilani Nathan moves to right flanker and Natalie Wright earns her first starting cap at halfback.No.8 Tabua Tuinakauvadra comes into the line-up to fill the void left by Duck, while Ashley Marsters returns to hooker with Naden unavailable.
Hoy now faces up to a year out of the game with her knee injury, putting her in doubt for the 2025 World Cup in England that starts in August.
"It's heartbreaking," Yapp said of the injury.
"She's an extremely popular member of the squad. She's kind, caring and professional in everything she does.
"We really feel for Bri."
Saturday's match marks the first time the Wallaroos will play Ireland since the 2017 World Cup.The Wallaroos will then travel to Cardiff on Sunday ahead of their next match against Wales at Newport Parade on September 21.
The Wallaroos then face Wales, South Africa and Scotland in the WXV tournament.Â