Russell has started all 11 games this season and is second on the Irish in tackles with 60, including 3.5 for loss. He has two interceptions and two forced fumbles as well. A fourth-year junior, Russell started all 26 games in his first two years with the Irish, in 2012 and 2013, before missing all of last season as part of an academics-related suspension.
He suffered the fracture late in the fourth quarter when he hit running back Tyler Rouse hard, knocking the ball loose with 70 seconds left.
Kelly said Russell will have surgery Sunday night to insert a rod in his leg, and the coach said it is unlikely that Russell could play again this season any time before a potential national championship game, on Jan. 11.
"He's one of those kids you hate to lose," Kelly said. "He's given so much to the program. We'll have to regroup."
The Irish previously have lost seven players to what Kelly has described as season-ending injuries.
Prosise leads Notre Dame with 1,032 rushing yards and 11 touchdowns, in addition to 308 receiving yards and one score. His 57 rushing yards against the Eagles put him over 1,000 yards on the season -- the fourth-quickest player to that mark in school history.
The redshirt junior, who had converted from wide receiver to running back this spring, had missed the majority of the Irish's previous two games with a concussion before returning Saturday against the Eagles. Prosise was injured when his left foot got caught under defensive lineman Connor Wujciak as he was being tackled in the second quarter.
Freshman Josh Adams has filled in for Prosise in the past, tallying 589 rushing yards and four touchdowns. The situation at cornerback is less clear, as Kelly said that junior Devin Butler, sophomore Nick Watkins and freshman Nick Coleman will all get opportunities this week to take over the starting role.
Kelly also said that junior starting linebacker James Onwualu is likely to miss his second straight game because of a second-degree MCL sprain in his left knee, while the coach is optimistic that sophomore defensive tackle Daniel Cage will return this week after missing two straight games with a concussion.
Information from ESPN staff writer Andrea Adelson and The Associated Press contributed to this report.