Mitchell limped from the field in just the 14th minute and did not return - but he had already made an impact on the match after scoring an early try.
After a disciplined first half performance the Dragons fell away in the second term, completing just nine of the 17 sets of possession as they crashed to a fourth consecutive loss.
The performance of rookie winger Mathew Feagai was one positive for the Dragons and he ran 198 metres with the ball, but errors proved costly for the Red V.
Rabbitohs halfback Lachlan Ilias continues to improve and he was one of his side's best in just his sixth NRL appearance.
Latrell Mitchell was all smiles as he crossed for his sixth try in as many matches against the Dragons after just six minutes following a long range break by Damien Cook. The NSW Origin hooker stepped Andrew McCullough and Aaron Woods after receiving an off-load from Jai Arrow and then beat Ben Hunt and Moses Mbye before linking with Campbell Graham, who found Mitchell in support.
It was a not so happy Mitchell just eight minutes later after limping out of a tackle by Woods and Tariq Sims. He immediately came from the field and did not return.
With Blake Taaffe filling the fullback role as he did during last year's finals series when Mitchell was suspended, the Rabbitohs barely missed a beat and would have scored again in the 16th minute if Graham could have held onto a Lachlan Ilias grubber in the Dragons' in-goal.
The Dragons had their chances, with a Zac Lomax no-look pass going to ground and a Jayden Su'A cut-out pass to Mikaele Ravalawa being above the Fiji winger's head.
Souths second-rower Keaon Koloamatangi gave his side a 10-0 lead at halftime after crashing over in the 34th minute.
The Dragons hit back after the interval after captain Ben Hunt grubbered into the Rabbitohs' in-goal on the third tackle and chased his kick to prevent Taaffe from getting back into the field of play and force a goal-line drop out. From the ensuing set of tackles, fullback Moses Mbye dummied his way over for a 48th minute try.
Hopes of a second half comeback were dampened when Graham scored just four minutes later after Koloamatangi pushed his nose through the defensive line and linked with Taaffe, who put the centre over out wide.
Rabbitohs captain Cameron Murray looked likely to have sealed his side's win when he crashed over 16 minutes before fulltime but the try was disallowed for an obstruction.
A 73rd minute Taaffe penalty goal gave Souths a 12-point buffer and Fiji centre Taane Milne made sure of the two premiership points after halfback Lachlan Ilias put him over three minutes before the fulltime siren.
Former Rabbitohs second-rower Jayden Su'A scored a late consolation try for the Red V after Murray stepped over the deadball line fielding the kick off from the Dragons.
Play of the game
Damien Cook ensured the Rabbitohs started the match on the front foot with two line breaks in the opening six minutes - the second of which led to a 50-metre try after he stepped past Andrew McCullough and Aaron Woods, beat Ben Hunt and shrugged off an attempted tackle by Moses Mbye before linking with Campbell Graham, who put Latrell Mitchell over.
What they said
"Latrell started the game really well so it was a worry when he went off but it is a hamstring injury so it's not too bad. He literally did in the run, he went to step off his left and he knew straight away that he had hurt his hammy. The good thing is that we got him off without any further damage. I thought it was a pretty special performance by Blake. For a kid who comes back in still under 10 NRL games and hasn't played or trained with the team for four weeks to play 65 or 70 minutes. I thought our defence was outstanding. I am pretty proud of that, and they had to because we were pretty dumb at times in the second half. We were a bit nervy but the two points is what we came here for ": Rabbitohs coach Jason Demetriou.