Manly's victory was comfortable on the scoreboard, but the aftermath could leave coach Geoff Toovey with an almighty headache leading into the finals.
They lost hooker Matt Ballin (calf) and prop Jason King (shoulder) in the first half, before David Williams (knee) and Jamie Buhrer (concussion) joined them in the casualty ward just minutes into the second half, leaving the Sea Eagles to play the final 36 minutes with no troops on the bench.
They lost that period of the game 16-4, but the damage had already been done in a blistering first half that saw the hosts head into the sheds with a 38-4 lead.
The severity of the injuries are still unknown, with the quartet to undergo scans this morning before an announcement on their immediate playing future is made.
Five-eighth Kieran Foran described it as a game of contrasting halves, elaborating on the difficulties of playing with the same 13 men for almost an entire half.
''It was so weird,'' he said. ''It couldn't have gone smoother that first half. Everything went to plan and everyone was feeling good. Then we got a few key injuries there. Matty Ballin went off then Buhrer goes off and you lose your ruck there with your hookers off the field.
''We were dropping like flies. Everyone was trying to play out of position and it wasn't working to well for us.''
Foran, as well as Glenn Stewart and Daly Cherry-Evans, all spent some time at dummy-half, while Jamie Lyon was forced to the wing and Anthony Watmough to the centres to combat the injury to Williams.
''It was a bit like the old days - once you come off, you're off,'' Toovey said. ''We ran out of troops there and the last 20 or 30 minutes we played with no reserves. It was difficult and a lot of players had to play out of position, which makes it hard for them, but we showed a lot of character and we got there.''
To add insult to injury, Tony Williams was placed on report for a trip on Knights centre Dane Gagai late in the game. The big back-rower, who played his best game since returning from injury against the Roosters in round 16, stuck a foot out trying to keep Gagai from crossing the try line in the 66th minute.
Knights coach Wayne Bennett, who admitted his side was never in the contest despite a spirited second-half showing, tipped Manly as one of the teams to beat in this year's premiership.
''I thought they were as good as anybody with credentials right now, I thought,'' the seven-time premiership-winning coach said.
''They may have taken a bit of a hit here today with some injuries. I'm not sure about the seriousness of their injuries, and if they lose a lot of players, then it will be too hard to get that right before the season's over, so I don't know that situation. But certainly their form - and I'm not saying that because of today's result - I'm saying it based on what I've seen in the last couple of weeks. They're playing the type of footy that wins when it matters.''
MANLY 42 (B Stewart 2 T Williams 2 K Foran J Lyon G Stewart J Taufua tries J Lyon 5 goals) bt NEWCASTLE 20 (K Naiqama 2 J Mullen A Uate tries T Roberts 2 goals) at Brookvale Oval. Referee: Jason Robinson, Phil Haines. Crowd: 14,191.