The 25-year-old rugby league convert will miss the rest of his debut AFL campaign after landing awkwardly when flying for a mark in the last quarter of the Tigers' 30-point defeat to Geelong on Saturday night.
Lefau, who was lively with two goals against the Cats, has been a shining light in a difficult season for Richmond, kicking 14 majors in 10 games.
Scans on Sunday confirmed the Tigers' worst fears for Lefau, who previously ruptured the ACL in his opposite (left) leg back in 2022 when playing VFL.
"Football can be a cruel game sometimes, and for Mykelti, who has been in terrific form, this is an unfortunate way for his debut season to finish," Richmond football performance manager Tim Livingstone said.
"Mykelti has not put a foot wrong since he joined our AFL program in the pre-season, and we know he will attack his rehab with the same professionalism and energy that has held him in such strong stead this season.
"We will give him our support every step of the way and help him to return to action and to continue with his promising career in 2025."
Dual premiership utility Marlion Pickett also suffered a calf injury and was subbed out of the match in the final quarter.
When leaving the field, Pickett raised his middle finger at a section of the crowd.
Coach Aem Yze was unaware of the incident but said he would speak with Pickett after viewing the footage.
"If he has, that'd be disappointing. I'll have a chat for sure. Can't be doing that," he said.
Richmond's Marlion Pickett appeared to raise his middle finger at a section of the Geelong crowd. (Julian Smith/AAP PHOTOS)
In his rookie season after following triple premiership coach Damien Hardwick at Richmond, Yze has endured a torturous run with injuries to his players.
Lefau and Pickett join the likes of Tom Lynch (hamstring), Tim Taranto (wrist), Jacob Hopper (hamstring), Jack Ross (foot), Maurice Rioli Jr (ankle) and Dylan Grimes on the sidelines.
Like Lefau, Tylar Young, Sam Naismith, Josh Gibcus and Judson Clarke have all been ruled out of the season with serious knee injuries.
"We've still got some young players that are getting some opportunities while we're going through this, so we're always going to look at the silver lining," Yze said.
Superstar Dustin Martin appears set to be rested for Richmond's trip to the Adelaide Oval on Thursday night to face the Crows.
Martin is only one game off becoming the seventh Richmond player to reach 300 games.
The triple Norm Smith medallist will almost certainly bring up the milestone the following week at the MCG against Hawthorn.
"It won't be around that (the milestone), it will be because we're going into a five-day break," Yze said.
"We'll probably have three or four players in that category based on their age and workload that might be high risk to play Adelaide no matter what.
"We're about performance.
"He'll want to play, but if it means it's too high a risk based on the five-day break and the travel; we'll make that decision later in the week."
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