Illinois (4-3, 1-2 Big Ten) ruled out Ferguson on Thursday night in its injury report.
Ferguson has missed two games after injuring the shoulder against Nebraska. Interim coach Bill Cubit said this week that he doubted Ferguson would be ready for the Penn State (6-2, 3-1) game.
Freshman Ke'Shawn Vaughn is again expected to be the starting running back. Vaughn is Illinois' leading rusher with 447 yards on 108 carries and four touchdowns.
The injury report also listed receiver Justin Hardee as now out for the season. Hardee was expected to be a starter this season but has not played since breaking his foot during the summer.