Hardesty, who missed all of training camp with a bone bruise in his right knee, was hurt on a 2-yard carry in the second quarter Thursday night against the Chicago Bears.
Hardesty stayed on the ground for several minutes before walking to the sideline. The team's medical staff examined him on a trainer's table before taking him to the locker room.
"I hurt my knee making a cut," a dejected Hardesty said after Cleveland's 13-10 win. "I really don't know what it is. I can't say it's not frustrating. I want to stay positive, get as much information as possible and return my focus to getting better. I'm hopeful whatever it is, I can get back as soon as possible."
Hardesty said it felt nothing like any of his previous injuries. He's scheduled for an MRI and more tests Friday.
Hardesty ran seven times for 25 yards and a 1-yard touchdown before leaving. He showed nice power on several inside runs, and powered his way into the end zone to tie it 7-7 in the first quarter.
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.
He had a major operation on his right knee in 2005.
Information The Associated Press contributed to this report.