Cruising at 16-0 midway through the first half, the Sea Eagles and Panthers engaged in see-sawing second half which saw the lead change hands a number of times, Penrith scoring two tries in the final three minutes to hand the visitors the win.
Had Manly won, they would have faced South Sydney on Friday night, the defeat giving them an extra day off ahead of the clash with the Roosters as the second game in the Allianz Stadium double-header.
But the Sea Eagles could certainly not be accused of tanking the game, having fought back valiantly twice late in the game, including David Williams's second try of the day with seven minutes to go to lock it up at 26-all.
From there the Panthers orchestrated a late entry for try of the year as they chanced their arm, a Luke Walsh kick finding Dean Whare in vacant space to put the visitors in front in the 77th minute.
Mose Masoe - who is heading to the Super League next year - added a parting gift as did Newcastle bound Clint Newton - who added the conversion to cap the win.
Manly debutant Clint Gutherson was among three Manly try-scorers inside the opening 24 minutes, but two tries to the Panthers before halftime made it 16-12 at the break.
A Josh Mansour try just after the restart had the Panthers in front for the first time, before Steve Matai scored his second to give the home side the lead.
Newton's angled run made it 24-20 to the Panthers - and for a team with nothing to play for Penrith were certainly keen on the win as they added a penalty to take it out to a converted try the margin.
PENRITH 38 (J Mansour M Masoe C Newton J Segeyaro L Walsh D Whare tries L Walsh 6 C Newton goals) bt MANLY 26 (D Williams 2 D Cherry-Evans C Gutherson S Matai tries J Lyon 3 goals).
Referees: Adam Devcich, Phil Haines.
Crowd: 12,090 at Brookvale Oval.