Hardesty, who missed all of training camp with a bone bruise in his right knee, was hurt on a 2-yard carry during the second quarter against the Chicago Bears.
Hardesty stayed on the ground for several minutes before walking to the sideline. The Browns' medical staff examined him on a trainer's table before taking him to the locker room.
The team said Hardesty's return was questionable.
The Browns are counting on Hardesty to have an impact in his first season. The team traded three draft picks to move up and take him in the second round. He ran for 1,345 yards last season at Tennessee, but his college career was slowed by knee injuries.
Hardesty had a major operation on his right knee in 2005.
Copyright 2010 by The Associated Press