Heading into round 12, the Knights and Manly had a league-worst 20 per cent win record in Origin-affected matches since 2016.
Queensland fullback Kalyn Ponga will miss Saturday's clash with understrength Penrith in Bathurst in the Knights' only change forced by Origin.
Newcastle have lost both games that Ponga has missed ahead of past Origin games, though have won three when he has been rested after Maroons appearances.
The Knights can also expect to be without Origin representatives for the second game of the series, held four days after their round-15 clash with the Sydney Roosters.
O'Brien has shifted Fletcher Sharpe from five-eighth to fullback.
The under-fire coach said Ponga's absence would prompt the Knights, already this season's worst attacking side by the numbers, to play "a lot less expansive".
"I anticipate we'll get Fletch in and around on the ball a lot more, he's a runner more than a passer," he said.
Even Ponga has been unable to spark the Knights this season, producing try assists in only three of 10 games.
O'Brien said his side could sometimes rely too heavily on their star fullback, and that his absence would be a test.
"Over-reliance? Yeah, you could agree with that," he said.
"He's a quality player and most players rely on their best strike weapons. But he's not with us this week so we have to adjust."
Making the task more difficult, the Panthers are the only side O'Brien has not defeated since taking charge in 2020, though the Knights did draw with Penrith that season.
Penrith are missing five players to Origin duty - the equal most of any team - but memorably defeated the Knights when they rested a slew of players after Origin II in 2023.
The four-time reigning premiers have slipped to 15th this season, and O'Brien felt both sides were similarly depleted given the Knights are missing Bradman Best, Greg Marzhew and Jacob Saifiti to injury.
"It sort of levels things out a little bit," he said.
"(The Panthers) stick to their structures really well. I don't expect them to change too much. They're a very good side at finding space in your defensive line."
O'Brien felt confident he had the support of the Knights' management regardless of the result on Saturday, when the Knights risk losing an eighth game in nine outings.
"I've got good, strong support from the board. They understand the situation we're in with our depth and the injuries," he said.
"That pressure and expectation comes with the job. I'm used to it now. We want results and I understand that our supporters and sponsors want results as well.
"But I can't get fixated on that narrative, I've just got to focus on getting today right and being really committed to fighting our way out with the players."