Graham has been left nursing a shoulder issue since last Friday's loss to the Sydney Roosters, and has not recovered in time to play on Saturday night.
Souths are hopeful the winger will return to play on Good Friday against Canterbury after next week's bye, but Moala Graham-Taufa will start in his place in Gosford.
His absence is one of two injury blows for the Rabbitohs, with Euan Aitken also set to miss the date with the Tigers while battling a cork injury that has left him unable to run.
Graham has endured a horror run in recent years, injured in the opening round of 2023 before playing through pain that entire campaign.
He missed the whole of 2024 following pre-season surgery on the injury, before a calf issue early last year eventually led to an operation on his back.
Graham had only spoken earlier this week about hoping he had turned a corner, with the body holding up well aside from general soreness after games.
"Footy comes with injuries and that's just part of the game we play," Graham told reporters on Wednesday.
"There were some tough times for sure, some long days, long weeks and long months. I'm lucky I am at a club where they give great care.
"I want to give a shout out to the medical staff who put me physically and mentally in a good place."
Graham-Taufa will play his sixth NRL match, replacing Graham, after debuting for the Roosters in 2021.
"He's not tall, but big," Bunnies coach Bennett said.
"They have done a great job with him at the Warriors, he's highly skilled.
"He'll get his opportunity tomorrow. I haven't seen a lot of him to make comment, but we're happy to have him here."
The other big in is Jamie Humphreys, after the Rabbitohs' first-choice halfback missed the opening two rounds through suspension.
After they were ravaged by injuries last year, Humphreys will now at least have the chance to steer a South Sydney team that are somewhat closer to full strength.
The 24-year-old spent part of his summer in Melbourne working with AFL clubs on his kicking, after going from a cut-price deal to claiming Souths' No.7 jersey last year.
"It was a great initiative by him and showed a real commitment by him," Bennett said.
"Combinations are everything in the game. We're only two weeks into the season but it's good to have him back."
Bennett also confirmed Souths expect to have hooker Brandon Smith back from a calf injury after the bye.
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