Manly could be forced to hand out up to three debuts against South Sydney, with their forward pack decimated and a total of 14 players unavailable.
The Sea Eagles will name one of the most injury-ravaged squads of the season on Tuesday, with only three of their first-choice starting pack and bench available.
As things stand, none of Manly's injured brigade from Sunday's gutsy win over St George Illawarra are expected to be able to face the Rabbitohs on Saturday night.
Reuben Garrick is a confirmed out with a concussion, while Taniela Paseka (thumb), Toff Sipley (knee) and Corey Waddell (ankle) all remain injured.
It comes with hooker Lachlan Croker still returning to training after the lingering effects of a concussion, and Matt Lodge sidelined with a bicep rupture.
Jake Trbojevic and Haumole Olakau'atu are both in NSW State of Origin camp, while Josh Aloiai remains sidelined for one more week for a needless trip.
Making matters worse for Manly, back-up forward Aaron Woods and Dean Matterson are also both unavailable through injury.
The drama leaves coach Anthony Seibold in a difficult position.
Mid-season recruit Jake Simpkin played 80 minutes at hooker on Sunday, which could potentially allow utility Karl Lawton to play in the back row or off the bench.
Second-rower Ben Condon is another player who could come in after scoring a hat-trick in NSW Cup on Sunday, while back-up hooker Gordon Chan Kum Tong is a bench option.
Prop Aitasi James would be one option to come into the NRL side, having impressed in NSW Cup since moving from Wests Tigers last year.
Otherwise, the only other forward in Manly's NSW Cup or Jersey Flegg team with NRL experience is Brad Parker, who has not played first grade since moving to the back row.
It means Manly could potentially have to start with a debutant in the front row, or up to two off the bench.
Seibold faces similar problems in his halves, with Daly Cherry-Evans on Origin duties, Jake Arthur injured and Blacktown-contracted player Brandon Wakeham stood down.
Luke Brooks is an option to captain Manly as their most experienced player this weekend, but no other available playmaker at the club has played first grade.
Unless Seibold opts for a makeshift five-eighth, highly touted youngster Jamie Humphreys is one option to make his NRL debut for the Sea Eagles.
Manly have better depth available in their backs, with mid-season recruit Aaron Schoupp 18th man on Sunday and a possibility to come into the centres.
Jaxson Paulo and Raymond Tuaimalo-Vaega have both also played first grade this year.
In better news for Manly, Tom Trbojevic is expected to return from his hamstring injury after their round-17 bye.
HOUSE OF PAIN: MANLY'S MISSING MEN
Tom Trbojevic (hamstring), Reuben Garrick (concussion), Daly Cherry-Evans (Origin), Taniela Paseka (thumb), Lachlan Croker (concussion), Josh Aloiai (suspended), Haumole Olakau'atu (Origin), Jake Trbojevic (Origin), Matt Lodge (bicep), Toff Sipley (knee), Corey Waddell (ankle), Jake Arthur (foot), Aaron Woods (calf), Dean Matterson (foot).
