St Kilda co-captain Jack Sinclair has a high-grade calf injury and it's unclear when he'll return to the AFL.
Sunday has had severe repercussions for the Saints as they try to stay in the finals hunt.
Apart from Sinclair's injury, big-name recruit Tom De Koning also suffered two fractured ribs and a punctured lung in their 22-point loss to the Western Bulldogs.
De Koning was sent to hospital as a precaution and scans confirmed his injuries.
While the Saints lost two key players and have a 6-9 AFL record going into their mid-season bye, there was also bad news out of their VFL win over Footscray.
Alix Tauru, who was dropped for the Bulldogs game, was booked for rough conduct and referred directly to the VFL tribunal for his bump on Stirling Phipps-Parsons.