In a thrilling finish, Souths trailed 18-10 with six minutes to go before Mitchell helped breathe life back into the Bunnies with a try off a Lachlan Ilias kick.
The Rabbitohs fullback was denied moments later when Nathan Cleary dragged him down from behind after a linebreak.
But Souths were still able to provide a last-gasp effort to win the game when Mitchell offered space on the left edge, Alex Johnston offloaded and Cody Walker put Isaiah Tass over.
The win marked only the Rabbitohs' second over Penrith in their last 12 matches, during a run that has often seen the Panthers come from behind to win matches.
For parts of Thursday night's clash it appeared it was going to be the same old story again for South Sydney.
Arch-nemesis Stephen Crichton scored all 18 of Penrith's points, including tries in the 66th and 71st minutes to take them from 10-8 down to 18-10 up.
There had even been a Crichton intercept-of-sorts off Walker, when he latched onto a kick from the five-eighth and went down field to put the Panthers on the attack for the back-to-back tries.
But unlike in the 2021 grand final when Crichton's hands had proved decisive, it would not be the difference.
Instead, the game-breaker was Mitchell.
The Souths superstar finished the match with 14 tackle busts and one linebreak, after playing a role in all four of the Rabbitohs' tries.
He got them on the front foot for their first when he put on a flick pass for Alex Johnston, before he bounded out of dummy-half on the next play.
He had his hands on the ball again later in the set, before Damien Cook darted over from dummy-half.
Then when the home side trailed 8-6 early in the second half, Mitchell did it all himself to put the Bunnies back in the lead when he beat three Panthers to score after a 10-metre scrum.
That all came before his heroics in the final six minutes, again emphasising why he is one of the most important players at South Sydney this century.
Ultimately it was enough to cancel out Crichton's brilliance for Penrith and Jarome Luai's threat in attack, handing the two-time defending premiers their third loss of the season and keeping themselves in the top four.
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