James Madison vs. Louisville Prediction, Odds and Key Players to Watch for College Football Week 2

Sean Treppedi | Sep 2, 2025

Louisville opens as 14.5 point favorites against a determined James Madison front on Friday. / Matt Stone/Courier Journal / USA TODAY NETWORK via Imagn Images

Louisville’s home opener brings a tougher test than the box score of Week 1 might suggest. 

The Cardinals rolled Eastern Kentucky with ease, but turnovers and a few shaky moments reminded everyone that Jeff Brohm’s group isn’t flawless. 

James Madison arrives as a motivated underdog, fresh off a dominant showing against Weber State that highlighted both its depth in the run game and its defensive discipline. 

With playoff dreams flickering in Harrisonburg and ACC validation on the line in Louisville, this is the kind of September clash that could shape both teams’ ceilings.

James Madison vs. Louisville Odds, Spread and Total

Odds via FanDuel Sportsbook

Spread

• James Madison +14.5 (-115)
• Louisville -14.5 (-105)

Moneyline

• James Madison (+430)
• Louisville (-600)

Total

• Over 57.5 (-110)
• Under 57.5 (-110)

James Madison vs. Louisville How to Watch

• Date: Friday, September 5, 2025 
• Game Time: 7 p.m. ET
• Venue: L&N Credit Union Stadium
• How to Watch (TV): ESPN2
• James Madison Record: 1-0
• Louisville Record: 1-0

James Madison vs. Louisville Key Player to Watch

Alonzo Barnett III, Quarterback – JMU

The redshirt sophomore wasn’t asked to do much against Weber State — just 130 yards and one touchdown through the air — but his efficiency fit perfectly in a run-first system that racked up 313 rushing yards. Against Louisville, however, conservative passing won’t be enough. The Cardinals have the front to clog up lanes and force Barnett into obvious passing downs, especially if Isaac Brown and the backfield set the tone early.

Barnett’s ability to extend plays with his legs and avoid negative-yardage mistakes becomes essential; one sack or interception could kill momentum against an ACC defense. If he proves capable of hitting intermediate throws consistently and keeping Louisville honest, James Madison’s balanced attack suddenly looks much more dangerous.

James Madison vs. Louisville Prediction and Pick

A two-touchdown spread feels inflated given what we know about both teams. Yes, Louisville has the higher ceiling — Miller Moss is a proven downfield passer and Isaac Brown can gash defenses in chunks — but Brohm’s track record as a big favorite is spotty. His teams tend to play to the level of the opponent, and even against Eastern Kentucky, miscues like a pick-six left the door cracked. James Madison, meanwhile, thrives on keeping games manageable with a defense that limits explosive plays; that travel-ready trait matters here.

If Barnett can manage the game and the Dukes’ front seven generates just a couple of key stops, this sets up for a competitive second half. Louisville’s depth might push them through late, but 14.5 points is asking them to dominate wire-to-wire. Backing the Dukes here isn’t a stretch — it’s a calculated bet that their physicality and discipline travel well enough to keep it close.

Pick: JMU +14.5 (-114 at FanDuel)

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Odds refresh periodically and are subject to change.

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