Louisville Cardinals vs Pittsburgh Panthers Prediction, Odds and Picks for Today, 09/27/25

The Louisville Cardinals are off to a 3-0 start, yet they are 0-3 ATS ahead of their trip to Pittsburgh to take on a Panthers squad fresh off a bye week after falling to rival West Virginia. Both squads enter this game ranking top-30 in total defense and top-35 in defensive efficiency. On the contrary, both offensive units fall outside the top-70 in efficiency.

Louisville and Pittsburgh both possess talented backfields, and I expect them to lean on the run game behind Isaac Brown and Keyjaun Brown for the Cardinals and Desmond Reid for the Panthers. For what it’s worth, the total has gone under in 3 of the last 4 meetings between these teams, and I expect the small sample size trend to continue; I’ll take the under.

Louisville vs Pittsburgh prediction: Under 57.5 (-110) available at time of publishing. Playable down to 56.5 (-110).

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