St Kilda have confirmed young defender Ben Paton suffered a double leg break when he was brought down in a tackle by assistant coach Jarryd Roughead.
The accident occurred during match simulation at training on Thursday, and is the latest in a series of injury blows for the Saints.
Ruckman Rowan Marshall (foot stress injury), captain Jarryn Geary (fractured leg) and youngster Ryan Byrnes, who had surgery to repair hamstring tendon damage, have been ruled out for at least the early rounds of the season.
Tough midfielder Zak Jones (hamstring strain) is in a race against time to be fit for the round-one clash with GWS on March 21.
Paton, who played 19 games last year, will miss the entire 2021 season.
The 22-year-old was treated on the ground at Moorabbin on Thursday and taken by ambulance to hospital.
"This is a devastating result for Ben," St Kilda chief operating officer Simon Lethlean said.
"He had such a strong year last year and had continued that form throughout the preseason.
"We know Ben will quickly turn his mind to rehab and how to get back out on the field as soon as possible, and he'll have our full support to do so."
Meanwhile, St Kilda coach Brett Ratten has revealed boom recruit Brad Crouch fronted his new teammates last month to address his off-season drug indiscretion.
Crouch is suspended for the first two weeks of this season after being caught with an illicit substance in September.
The 27-year-old was still an Adelaide player at the time, and joined the Saints as a restricted free agent in November.
"He had a chat to the group fairly early when he got back after Christmas," Ratten told AFL Media.
"It builds a connection straight away.
"Brad's accountable to that as well, which is pretty important, and it shows respect for the football club straight away."