Star fullback Upton, important winger Julia Robinson and front-rower Makenzie Weale will all miss next Thursday's clash on the Gold Coast after sustaining unspecified injuries in Origin II.
Uncapped duo Destiny Mino-Sinapati and Lillian Yarrow both come into Nathan Cross' squad for the final game of the 2026 series.
Gold Coast's Mino-Sinapati has the lofty task of replacing the NRLW's best player at fullback, while Brisbane recruit Yarrow will come off the bench.
Shenae Ciesiolka is promoted from replacement player and onto Robinson's wing.
"We know the strength and quality that exists within this group and while it's been tough not to come away with the wins so far, the performances have shown exactly what this side is capable of," said Maroons coach Cross.
"It's also been really exciting to see some of the younger players and debutants come into the environment and handle the Origin arena so well."
The Blues have named the same 17 that wrapped the series up with a 14-10 game-two win at Suncorp Stadium last Thursday night.
Cronulla's Quincy Dodd will slot into the reserve's No.18 jersey for Corban Baxter, who will wear No.19.
Versatile NSW veteran Tiana Penitani Gray remains out with the knee injury that prevented her from lining up in Origin II.
The Blues could become the first NSW Origin team - men or women - to claim a 3-0 series sweep since 2000.
Neither women's team has achieved the feat since the Origin series expanded to three games in 2024, with NSW falling short in their game-three loss last year.
"The fact that we got it done in two, which we did last year, certainly doesn't make it any easier," NSW coach John Strange said on Wednesday.
"People call them dead rubbers and whatnot, but they certainly aren't dead rubbers, and there's a lot of pride on the line.
"It's incredibly hard (to win 3-0), and we know that through firsthand experience last year, how difficult that is. So we're certainly up for the challenge."
NSW SQUAD:
Abbi Church, Jaime Chapman, Jess Sergis, Isabelle Kelly, Jayme Fressard, Jocelyn Kelleher, Jesse Southwell, Millie Elliott, Olivia Higgins, Ellie Johnston, Kezie Apps, Yasmin Meakes, Olivia Kernick, Keeley Nizza, Kennedy Cherrington, Rima Butler, Teagan Berry, Quincy Dodd, Corban Baxter, Hannah Southwell
QUEENSLAND SQUAD:
Destiny Mino-Sinapati, Shenae Ciesiolka, Rory Owen, Ivana Lolesio, Jasmine Peters, Chantay Kiria-Ratu, Lauren Brown, Otesa Pule, Destiny Brill, Jessika Elliston, Sienna Lofipo, Romy Teitzel, Keilee Joseph, Emma Manzelmann, Brianna Clark, Lillian Yarrow, Jada Ferguson, Chelsea Lenarduzzi, Sophie Holyman, Georgia Ravics.
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