The Panthers are now four points clear of the second-placed Warriors after NSW debutant Casey McLean bagged two tries at CommBank Stadium.
McLean, who made his Blues debut off the bench on Wednesday night following Tolu Koula's injury, was the only Penrith or Warriors player who featured in the Origin opener to return to club action.
Panthers coach Ivan Cleary opted to sit Nathan Cleary, Isaah Yeo and Brian To'o out of Sunday's top-of-the-table clash, while Warriors counterpart Andrew Webster rested Kurt Capewell and Mitch Barnett.
But Penrith (11-1), led by some heroic plays from Dylan Edwards, didn't need their big guns to further underline their credentials as NRL premiership favourites in one of the games of the season.
Edwards, overlooked for NSW selection and handed captaincy duties with Yeo and Cleary sidelined, came up with the play of the game in the final 15 minutes, stopping Jacob Laban then setting up Paul Alamoti to complete a double with the match-winning try.
"It was a great captain's knock (from Edwards) and he does it most weeks, to be fair," said Ivan Cleary.
"I think everyone played their part and when we're without the guys we're missing, it's important that your leaders step up.
"(McLean) was probably the difference and I was hoping after Wednesday night that he'd get that extra (level).
"It's all very well to say you've got the next-man-up mentality, but you've got to show it."
The victory in front of 17,640 fans continues Penrith's strong post-Origin record, with Cleary's side having won 12 of their past 14 such fixtures since the start of the 2021 series.
McLean had an instant impact when he came off the bench for his Blues debut on Wednesday and could come into calculations for a starting berth if Koula fails to recover before NSW coach Laurie Daley names his side for game two on June 17 in Melbourne.
And it took the new NSW star just six minutes to breeze over against Webster's side.
Laban hit back for the Warriors and the Panthers were walking a tightrope with the Kiwi outfit placing the home side under heavy pressure for large swathes of the first half.
Ali Leiataua and Adam Pompey had tries rightfully chalked off but Penrith pulled away as halftime neared, with McLean and Alamoti touching down to give them a 16-6 lead at the break.
Taine Tuaupiki pulled the Warriors within touching distance before an Alamoti blunder allowed Alofiana Khan-Pereira to stroll in.
Pompey made no mistake with the boot to put the Warriors 18-16 up with 20 minutes to go.
But Edwards dragged his side back into the game and to victory.
First he stopped Laban with the tryline beckoning, then he sent Alamoti in for his second try with a beautifully-delayed pass in the 70th minute.
The Warriors had one last crack at the Panthers' line but McLean jolted the ball loose from Tuaupiki and Penrith held on for victory.
"We look likely in control and then we'd let them off and they're too good and they punish you," Webster said.
"We're trending like a good team but we're not the finished article that's for sure."
