Derrick Henry faces foot surgery on Tuesday after suffering what could prove a season-ending injury in the Tennessee Titans' win over the Indianapolis Colts.
The star running back is reported to have suffered a broken bone, with Titans coach Mike Vrabel saying Henry will "work extremely hard to get back".
The Titans have leaned on Henry as the focal point of their offense for the last three seasons and his absence will come as a major setback.
Tennessee improved to 6-2 with their 34-31 overtime victory in Indianapolis on Sunday, but Henry was placed on injured reserve a day later.
"Derrick is going to have surgery in the morning [on Tuesday]," Vrabel said, quoted on the Titans' official website. "We are not going to put a timeline on when he may return.
"I know that he'll do everything that he can to work himself back, to be able to help this football team. And whenever that is, that's when it will be."
This year, Henry has produced consistency that was putting put him in position to threaten Eric Dickerson's 1984 record of 2,105 rushing yards in a single season.
He leads the NFL with 937 yards, 288 more than his nearest challenger, the Colts' Jonathan Taylor.
Henry carried the ball a league-leading 303 times in 2019 and increased that number to 379 last season, winning the rushing title in back-to-back years.
The former Alabama star had already tallied 219 rush attempts this season, putting him way out ahead in the NFL, with backup Jeremy McNichols used predominantly as a pass-catcher.
Vrabel said: "We'll have to move on unfortunately without him in the short term, and not look back. I hate to speak for our players, but Derrick is disappointed, everybody is.
"We spent a lot of time together with the coaching staff and with the players, so you never want to see any of them injured in any capacity. So I know that Derrick is going to work extremely hard to get back to do everything he can to help this football team."
Dickerson's record no longer appears to be in any danger, and the AFC South-leading Titans are likely to put an increased burden on quarterback Ryan Tannehill in Henry's absence.