The Dragons fell to the Rabbitohs 28-22 at Accor Stadium amidst significant challenges.
They faced an astonishing five failed HIAs, keeping their medical team on high alert.
Ha'ele Finau and Cyrus Stanley-Traill both sustained head injuries in the first quarter.
Lyhkan King-Togia was added to the list early in the second half, followed by Nathan Lawson and Nick Quinn.
Despite these setbacks, the Dragons showed resilience, coming close to a converted try in the final moments.
Tyler Peckham-Harris ended the match in the halves, paired with Declan Purcell, while Tom Kirk moved to the back and Dylan Coutts took up right centre.
South Sydney quickly retaliated, with Bayleigh Bentley-Hape crossing the line to regain the lead.
A Dragons error on kick-off allowed the Rabbitohs to capitalize, with Mazzone scoring in the corner to extend their advantage to 16-6.
Treweek scored again for the Dragons just before halftime, capitalizing on a deflected grubber, while Tom Kirk's conversion reduced the gap to four.