The rookie running back was initially diagnosed with a sprained MCL, but further testing revealed the torn ACL, according to Ian Rapoport of NFL Network.
Following Thursday's 26-17 loss, Guice told reporters he "felt good" and downplayed the severity of the injury.
"At the back end of the play, when I was stiff-arming [a defender], my feet just kind of planted weirdly on the turf and my knee just hyperextended a little bit," he said, per ESPN.com's Mike Reiss. "It's fine."
Prior to leaving the field, the LSU product picked up six carries for 19 yards. He also had a 34-yard run called back because of a penalty. Incidentally, that was the same play on which the injury occurred.
"We tried to get it going for him and he popped a long run and unfortunately I think he's got a leg thing that got caught up in the turf," head coach Jay Gruden said after the game on Thursday, per Pro Football Talk's Mike Florio. "It's just one of those unlucky plays that unfortunately happens to all players from time to time."
Now, Washington will need to rely on a committee of Rob Kelley, Chris Thompson and Semaje Perine to fill the void. Guice was drafted in the second round of the 2018 NFL Draft to give the team a more dynamic presence in the backfield, but the team has enough depth to maintain with Guice on the sideline.