Since making the switch to Elland Road in the summer of 2023, Ampadu has proven to be a key player for head coach Daniel Farke.
A total of 53 starts have been made in the Championship, as well as a further eight outings coming in other competitions.
Either as a centre-back or central-midfielder, the Wales international has made an impact, but Leeds must now make do without his services for at least three months.
In the first half of Saturday's fixture against Coventry City, the 24-year-old needed to be withdrawn, and it has since been confirmed that he will spend a significant period on the sidelines.
Farke comments on Ampadu injury
Speaking to BBC Radio Leeds, Farke has suggested that Ampadu may be in a position to return in the first month of 2025.
The German said: "It's a serious knee injury, he has damaged his lateral ligament - the doctors have recommended a conservative treatment so he doesn't need surgery.
"It's difficult to predict how long he will be out but it's realistic to speak about 10 weeks until he can return to team training.
"It could be a few days more or less depending on the rehab. At the moment we expect him to be back in training at some point in December but he will need a bit of team training before he's available.
"We expect him to be back [playing] at some point in January."
Who will replace Ampadu?
Summer arrival Ao Tanaka is the natural replacement for Ampadu in the engine room, albeit with the Japanese yet to make a start in the Championship.
Prior to his 49-minute outing at the weekend, the former Fortuna Dusseldorf man had been introduced no earlier than the 86th minute in his previous three outings.
Joe Rothwell is another alternative, the 29-year-old having also been restricted to substitute appearances (seven) since moving to the Yorkshire giants.