After turning it on at the start of an impressive first half, Ponga limped off with a hamstring tear before Brown followed soon after with medial damage to his knee.
Both are due for scans, with Ponga uncertain how long he will spend out, while Brown's injury is expected to sideline him for up to a month on initial assessment.
Their injuries marred what was an otherwise dominant performance, against a Manly side that is now 0-2 with coach Anthony Seibold likely to face pressure.
Newcastle are 2-0. They also won their first two games last season, but appear a different side under new coach Justin Holbrook.
And Ponga has been at the forefront of it, alongside the Knights' big-money signing Brown.
Ponga played a role in all of Newcastle's first three tries, finishing off their third and injuring his hamstring in the process.
The fullback helped Bradman Best send Greg Marzhew in for the Knights' first, before trampling defenders in the lead up to combining with Brown to lay on Newcastle's next through Dom Young.
And while Manly hauled the deficit back to 12-10, Ponga was hurt when he fended off Jason Saab and dived over to make it 18-10 following a long-range Best bust.
"There was a bit of an overstride when I made that palm," Ponga said.
"At least we scored. It's not ideal two playmakers going down, but the boys did the job for us massive.
"Last time I did a hammy was 2018 I think, so I don't really know (how bad it is). Fingers crossed it's best news, I want to be back out there next week."
Brown suffered medial damage 10 minutes later while sending Fletcher Hunt over for the Knights' next, hurt in contact from Tom Trbojevic after breaking the line.
Newcastle may have Fletcher Sharpe back next week against the equally-unbeaten Warriors, where he can play either fullback or five-eighth.
Woeful in attack last year, Newcastle averaged just 14 points per game and posted 30 points in a match just once. This year, they already have scores of 28 and 36.
"We're quite clear on our roles," Ponga said.
"Our middles do a great job at keeping us in the game, and then our spine, we're pretty connected. I just think the clarity is there at the moment."
Manly have all sorts of issues, after a miserable Sunday afternoon at home.
Luke Brooks let the opening kick off go dead and the day hardly grew any better from there, with the Sea Eagles trailing 30-10 at the break and barely landing a blow in the second half.
Trbojevic showed some fight as he got it back to 12-10 when he ran over from a scrum, but the No.1 spilled a bomb in the lead up to gift Tyson Frizell before halftime.
And while a Trbojevic offload for Haumole Olakau'atu made it 30-16 after the break, Brooks again dropped the subsequent kick off and Young scored in the next set to seal Manly's fate.
"No one ever means to make an error, but our ability to then show resolve off the back of that is what we're searching for," Seibold said.
"I've been 0-2 before and been a top-four side.
"The really good teams in the competition win at 60 per cent, the good teams win at 50 per cent. There's another 22 games to go."
25°C