Anderson, who has started every game this season and recorded two tackles against the Bearcats, sprained his knee in the second half of seventh-ranked Louisville's, 23-17, win over rival Cincinnati.
Anderson will likely miss next weekend's game against Syracuse and probably won't return to the field until sometime next month.
"It's a knee sprain and I think it's much like what Abe Brown had last year," Louisville coach Bobby Petrino said. "He'll certainly be out for a while, maybe four weeks, and that's not good. He's a leadership and effort guy for our team."
The Cardinals have overcome injuries on defense the entire season. Defensive linemen Adrien Grady missed several games because of injury, as did redshirt freshman Jonathan Holston. Cornerback Rod Council missed three games earlier this season, Brown didn't play against Kansas State. Fortunately for Louisville, all four of those defenders have returned to action.
Now, the Cardinals will have to pick up the slack with Anderson sidelined.
"I almost cried on the sideline. That is my buddy (Zach Anderson) and roommate," senior defensive tackle Amobi Okoye said. "I will be in his ear about rehab. I've got to play for him, play for our fallen soldier."