During the closing days of the summer transfer window, Leeds moved to strengthen their squad with the loan acquisition of the Tottenham Hotspur right-back.
The 23-year-old subsequently made his debut as a late substitute during the goalless draw with Sheffield Wednesday before the international break.
Given his previous impact in the Championship, Spence was in contention to start against Millwall on Sunday, but he was a notable absentee from the squad.
On Monday, Leeds revealed that Spence picked up a knee injury in training last week, ruling out him of the trip to The Den and for the foreseeable future.
A club statement read: "Leeds United defender Djed Spence picked up a knee injury following a challenge in training last week, and following scans, we can confirm he has damaged his lateral collateral ligament.
"The injury is not expected to require surgery and we expect Djed to return to play within eight weeks."
While Leeds went on to see off Millwall by a 3-0 scoreline on Sunday, the injury is a blow to both the player and head coach Daniel Farke.
Spence endured a frustrating 2022-23 campaign, making just six substitute appearances under Antonio Conte before being loaned out to Rennes in January.
The former Nottingham Forest loanee racked up nine starts and one substitute outing during his time in France before returning to Spurs, where Ange Postecoglou deemed him to be surplus to requirements.
From Farke's perspective, the German would have felt that he had pulled off one of the second-tier signings of the summer with Spence having previously helped Forest to promotion in 2021-22.
Instead, he will now have to rely on other options, Luke Ayling having started each of Leeds' Championship fixtures at right-back this season.
Sam Byram will act as backup to Ayling despite his game time having come on the opposite flank since he rejoined Leeds in the summer.