The Adelaide pick-up was set to return from his second ACL rupture in Thursday night's high-stakes Gabba clash - a timely addition given injuries to fellow backs Keidean Coleman and Conor McKenna.
The 27-year-old will now join them on the sidelines and possibly require surgery after an "innocuous" incident in the final moments of Tuesday's training session.
Scans confirmed a partial tear in his right ACL, the same one he ruptured last season while playing for the Crows.
Doedee had already recovered from an ACL tear suffered in 2019.
"It's incredibly heartbreaking for Tom, and everyone at the club is really feeling for him," Lions football boss Danny Daly said.
"Sport can produce some of the most amazing moments, but in cases like this it can also be extremely cruel.
"Tom is a fantastic person who has already become a highly popular member of our club, and everyone was excited to see him so close to making his comeback."
Doedee, who played in the Lions' VFL team at the weekend, will consult a surgeon to determine his best course of action.
Lions coach Chris Fagan missed the fateful training session on Tuesday after he flew to Melbourne to attend conciliation sessions at the Human Rights Commission alongside former Hawthorn players.
Along with the injuries to Doedee and Coleman, young gun midfielder Will Ashcroft is also recovering from an ACL tear and won't return for the Lions until later in the season.
"He (Doedee) has been in full training for six or seven weeks," Fagan told reporters in Brisbane on Wednesday.
"We were looking forward to having him as part of our team, but unfortunately that's not going to be the case this year.
"The last 10 rounds of footy we've played, we've lost three blokes (Doedee, Coleman and Ashcroft) with ACLs.
"I've never seen a strike rate like that. I hope it stops. This is the game, you've got to deal with it."
Doedee on Monday said his knee had given him no trouble during Saturday's VFL return.
"This time I feel stronger. I feel a lot more mature and a better athlete … and have a better sense of the game after having a year out," he said.
"The knee felt good, back out with the boys, and it was just overall a good feeling after a pretty long and arduous 10 months."
The Lions copped a brutal opening-round blow when they coughed up a big lead to lose by one point to Carlton, Coleman's own season-ending ACL tear compounding the pain.
They were then outplayed in Perth by Fremantle and, after a bye, face premiers Collingwood (0-3) on Thursday, with both sides seeking their first win of the season.
Fagan admitted he would be "amazed" if the Lions weren't back to their best to confront the team they lost to by four points in last September's decider.
"It's probably human nature when you lose a grand final by not much, that all you can think about is getting back there and trying to make up for it," he said.
"Our players aren't ill-disciplined or poor human beings for thinking that way, it's natural.
"Whether that's good enough to win, who knows, because it's two good teams playing each other in the same position."
