The Sea Eagles confirmed on Tuesday that Trbojevic would captain the Sea Eagles against the Knights, reclaiming the No.1 jersey after a knee injury to Tolu Koula.
Anthony Seibold will also run out a recognised playmaker at halfback in Humphreys, who will partner Luke Brooks with Daly Cherry-Evans in Queensland camp.
Manly have the worst record in the NRL in State of Origin-affected rounds, winning just one of nine games without their representative players since 2016.
The Sea Eagles used a makeshift half in Tommy Talau in their last Origin-affected match against South Sydney, but failed to score a point while severely depleted.
But this time around, Brooks believes Manly will be better placed with Humphreys alongside him at No.7.
Luke Brooks (pictured) is looking forward to playing alongside Jamie Humphreys. (Dave Hunt/AAP PHOTOS)
"He's a great player," Brooks said.
"The way he trains, he trains so hard. You know what he's going to bring to you. We have plenty of trust in him if he does play.
"It's hard. Tommy (Talau) has played centre and wing his whole NRL career.
"To step up and play in the halves, it's a tough job. If we do go with a genuine half, it will help."
Humphreys' debut comes despite the 22-year-old having already signed with South Sydney for next season.
Brooks said the team have also learned from the gritty affair against the Rabbitohs.
"It was just a bit about detail we need to fix up," he said.
"We had a few players out and our attack wasn't where it has been all year. Learn a fair bit off that and we'll get that going into this week.
"I've (taken on the controlling role) pretty much my whole career, so it's nothing new to me.
"Obviously we lose a lot with 'Chez' going out, but I've done it my whole career."
Meanwhile, Trbojevic's shift back to fullback comes after Manly had planned on him playing in the centres for a month on return from his latest hamstring setback.
But Koula's injury has changed those plans, with Trbojevic to wear No.1, Lehi Hopoate coming in on the wing and Talau going to centre.
Tolu Koula will miss six weeks after surgery on his medial ligament. (Scott Radford-Chisholm/AAP PHOTOS)
Koula will require surgery on his medial ligament and miss six weeks with the injury, after he was hurt in the sixth minute of Saturday night's 21-20 win over Gold Coast.
The fullback played on through the pain, still running 309 metres with ball in hand.
"You wouldn't know he got injured in his first tackle," Brooks said.
"It just shows how tough he is. He did something similar when he went to fullback in the Broncos game, he did his shoulder and played on with it."
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