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.
Tauru faces a ban of at least three games.
There was good news on ruck-forward Rowan Marshall, who suffered a shoulder injury.
Marshall played out the game and the Saints said scans cleared him of serious damage.
Sinclair was cleared of an achilles injury, but the early prognosis on his calf was not encouraging.
"Sinclair will miss an extended period and will be re-assessed over the coming weeks to determine a timeline for his return," the club said in a statement.
Saints football boss Lenny Hayes also said De Koning faced a "challenging recovery" from his chest injuries.
"Despite Tom initially showing no signs of internal damage, our decision to send him to hospital was taken with every precaution," Hayes said.
Adding to a dirty day, St Kilda star Nasiah Wanganeen-Milera can accept a $1000 fine for "flipping the bird" to a section of the crowd late in the game at Marvel Stadium.
