A 57th-minute Cody Walker try briefly widened the margin, before Dallin Watene-Zelezniak replied to give the home side more hope.
A Dane Gagai four-pointer in the 73rd minute looked like a game-sealer, only for Viliame Kikau to brush aside five defenders and set up a grandstand finish.
Penrith had a couple more chances to steal the win, however were left to rue a fifth loss from their opening seven matches of the season.
They could finish as low as 14th by the end of the round, and have the daunting task next week of tackling high-flying Canberra.
It comes at the end of an emotional week due to the shock exit of the man who single-handedly saved the club from insolvency in Gould.
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The premiership-winning coach, who was given a standing ovation by some fans during a tribute pre-game, watched from the stands at Panthers Stadium.
For the Rabbitohs, the two points ensures they keep pace with ladder leaders the Sydney Roosters and Melbourne.
It was a hard-fought victory for Souths, who had to defend 55 plays inside their 20-metre zone compared to the 14 looks they had at the other end.
Both sides started at a cracking pace, but the Panthers opened up early when Kyle Turner ran over Nathan Cleary for first points.
Their lead doubled via a Dane Gagai miracle ball in the 20th minute. He poked through two defenders before popping a pass, while falling, for Corey Allan.
Penrith thought they had their first try when James Fisher-Harris pounced on a grubber, but it was taken back due to an incorrect play-the-ball.
In the end, the Panthers went into halftime try-less, however gained some spark soon after the resumption when James Maloney went over from close range.
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Despite his team slumping to another defeat, Cleary described their display as the best of their season so far.
“I feel like it’s something we can definitely build from. We looked likely the whole game, we couldn’t quite take our chances,” he said.
“Credit to Souths. They came up with some big defence time after time and they were good enough to take their chances.”
Rabbitohs coach Wayne Bennett praised his team’s defence.
“It’s a bit weird, isn’t it? We did give up three tries but they just had an unbelievable amount of ball and a lot of repeat sets,” he said.
“From in-goal stuff, we either touched the ball or knocked one on and they got it straight back. It was pretty gutsy in the end.”