The Knights have had to count the cost of a rousing 30-6 victory over Brisbane last round, as Best emerged from the clash with a low-grade calf strain.
The NSW State of Origin representative's injury will be unwelcome for Newcastle (12-8), who sit just two points clear of ninth place and are looking to win prop Tyson Frizell's 300th match on Sunday at GIO Stadium.
Best's niggle is the latest setback in a stop-start campaign as he's also battled through groin and calf injuries earlier in the season.
Fletcher Hunt will shift into the centres while teenager Toby Winter moves onto the bench.
Newcastle's news comes after Canberra coach Ricky Stuart said their hopes of victory will rest on halfback Ethan Sanders' kicking game.
The Raiders (9-11) must snare a victory on Sunday if they are to have any chance of securing a winning record and staying in contention for the NRL finals.
However, the weather is set to cause chaos with torrential rain expected to impact the playing surface.
It means the 11th-placed Canberra's usual razzle dazzle, hard running and fast game will have to be tweaked, and Stuart is relying on Sanders to pick up some of the extra work.
After a rocky start to the year, the young halfback has begun to find his groove with his booming kicks becoming crucial to the Green Machine's winning formula.
"It (kicking game) is important in every game, but when you're playing in wet, slippery conditions it is important," Stuart said.
"You're going to play a little bit of a different style of game, but we've seen the forecast.
"It was meant to be very windy and now it's probably forecasted not as much wind, but it's going to be wet here."
The Raiders welcome back centre Simi Sasagi from a hamstring strain as they look to rebound from a dismal 42-18 loss to Penrith last Saturday.
Along with Sasagi, second-rower Joe Roddy is poised to play his first game off the bench since he broke his hand in round nine and underwent surgery.
"Then last week, there was something wrong with his ankle or whatnot," Stuart said.
"It's been disappointing that he hasn't got more game time this year because it's what's needed for him at this stage of his career.
"But it's good to have him back now. He's a good trainer. He's a great bloke to have around the camp."
15°C