Cronulla matched - and for large periods outplayed - Penrith in round 19, and were in the match right up until Jarome Luai's 77th-minute try put the game beyond reach.
The Rabbitohs head to PointsBet Stadium in red-hot form, having won their last four matches including a 24-12 victory over the Storm last weekend.
The two clubs have met just once a year for the past six seasons, with South Sydney winning four of those clashes.