Murray will have surgery Monday to repair a hamstring tear in his left leg.
Oklahoma will play Florida Jan. 18 for the major college football championship.
"Obviously we're very disappointed for DeMarco," Oklahoma Coach Bob Stoops said Tuesday. "He has been an important part of our success this year and we will miss his contributions. DeMarco has had an incredible year."
A report from the university said Murray, who injured his leg in the Sooners' 62-21 Big 12 championship victory against Missouri, will need five months of recovery time after the operation on his leg.
Murray has run for 1,002 yards and scored 18 touchdowns this season.
Chris Brown, the team's leading rusher, and Mossis Madu, who replaced Murray, will be Oklahoma's main ball-carriers against Florida.
"With Chris Brown and Mossis Madu, we still have two very fine backs," Stoops said. "Our team has a lot of confidence in their abilities."