In a news release, Creighton described the injury as a "partially torn medial collateral ligament and patella injury" in Zierden's right knee.
He suffered the injury during the first half of Wednesday's loss at Butler.
A decision has not been made on whether Zierden will undergo surgery, but the injury could require six months to heal, the release says.
The sophomore was sidelined for the final seven games of last season after suffering a dislocated right kneecap.
Over 20 games this season, Zierden has ranked second on the team with 9.5 points per game while shooting 39.6 percent from three-point range and 90 percent from the free-throw line.
Creighton (9-11) has lost eight consecutive games. The Bluejays will play at No. 4 Villanova on Sunday.