The reigning premiers were stung by losing important trio Harris Andrews (three matches), Darcy Gardiner (one) and Zac Bailey (one) to suspensions out of the season-opening defeat to the Western Bulldogs.
Hugh McCluggage went down with a calf strain and the Lions were dealt a further blow when young key forward Logan Morris, who kicked three goals against the Dogs, was ruled out of Saturday night's trip to the SCG with a fractured hand.
It will be the first time dual premiership coach Chris Fagan - now in his 10th season at the helm - will lead Brisbane with both Andrews and McCluggage out of the team.
"The good thing about us is there's a lot of great depth and a lot of players ready to go," Lions forward Kai Lohmann said on Thursday.
"We have players that can come in and play a role and hopefully the boys that come in can do a good job.
"I'm really excited for those boys to get an opportunity."
Former Essendon ruck Sam Draper will play his first game for Brisbane against the Swans, after overcoming his achilles injury and foot stress reaction.
Lions Academy product Daniel Annable will debut after he was taken with pick No.6 in last year's draft, while McCarthy will play his first game since May 2024.
The 32-year-old missed Brisbane's back-to-back premierships with successive serious knee injuries.
"He's been pretty unlucky with injury, so it'd be a huge lift," Lohmann said of McCarthy's return.
"He's a cult hero at the club."
Noah Answerth and James Tunstill are also back for Brisbane, while Sydney named an unchanged team after thrashing Carlton in the opening round.
Elsewhere, Geelong have regained Jeremy Cameron (quad) and Patrick Dangerfield (calf) from injuries for their home clash with Fremantle on Saturday, but lost midfield recruit James Worpel (infected finger).
The Dockers named tall pair Sean Darcy and Luke Jackson in their starting midfield and captain Alex Pearce has shrugged off a calf injury.
The Western Bulldogs picked mature-age recruit Will Lewis to debut against GWS and Ryley Sanders returns, with Arthur Jones and Jordan Croft out injured.
The unchanged Giants named Finn Callaghan despite the sore midfield star missing training on Thursday.
Collingwood picked star forward Jamie Elliott to play against Adelaide on Saturday night despite his illness, while key backs Darcy Moore (calf) and Jeremy Howe (calf) are still sidelined.
Brisbane premiership star Callum Ah Chee will play his first game in Crows colours.
On Friday night, Ned Reeves and Cam Mackenzie return for Hawthorn against Essendon, with Harry Morrison and Finn Maginness dropped.
First-year Bombers Dyson Sharp, Max Kondogiannis, and Huss El Achkar will all debut in front of about 90,000 fans at the MCG.
West Coast will unveil their top three draftees from last year against Gold Coast on Sunday, with No.1 pick Willem Duursma, Cooper Duff-Tytler (No.4) and Josh Lindsay (No.19) all confirmed starters.
Just two weeks after joining the club, pre-season supplemental selection Milan Murdock will make it a quartet of debutants for the Eagles in round one.
Mature-age recruits Tom Blamires and Jack Watkins will debut for North Melbourne and Port Adelaide respectively in their Marvel Stadium clash.
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