Early James Madison vs Louisville Predictions, Picks & Odds for Week 2

Chris Hatfield offers his early James Madison vs. Louisville predictions ahead of Friday’s clash.

Sep 1, 2025 • 18:53 ET

• 4 min read

Being a two- to three-touchdown favorite hasn’t always resulted in a straightforward game for Louisville head coach Jeff Brohm, and he’ll find himself in that position when Louisville welcomes James Madison.

The Cardinals will take care of business, and in the end, it may be rather than convincingly. However, that doesn’t mean the game will be entirely free of stress.

I break it all down in my early Louisville vs James Madison predictions and college football picks for Friday, September 5th.

James Madison vs Louisville predictions

Here are our early thoughts on the spread and total for this week’s game. We will have a full game preview (with a best bet and SGP) later in the week.

Early James Madison vs Louisville spread pick: James Madison +14.5 (-112)

Taking anything away from last week’s Louisville game is a fool’s errand. The Cards thumped FCS opponent Eastern Kentucky, scoring 50+ points, with the game appearing slightly closer on the scoreboard than it ever was. USC QB transfer Miller Moss looked in control of the offense, RB Issac Brown continued to stake his claim as one of the best backs in the country, and a Brohm–coached team did what a typical  Brohm–coached team does with explosive offensive plays.
 
This week is an entirely different conversation. The hallmark of the Brohm era at Louisville has been some great upset wins, but also some surprising performances against bad to average opponents. At Louisville, he’s covered just once in that two-to-three-score range, and his career ATS mark as a double-digit favorite across Louisville and Purdue sits at 8–11. Compare that to Louisville’s 9–5 record in the same role while he was at Purdue, and the trend is clear: Brohm doesn’t consistently bury weaker teams.
 
Trends are useful, but with rosters evolving more than ever, they simply matter less than they ever have. James Madison has been a popular Group of Five pick to make noise, and they do what’s essential against Louisville: limit explosive plays. They ranked just outside the top 50 last season in 20+ yard gains allowed (52 total) and should improve defensively. Am I rushing to bet on this? No. Louisville could still tack on late points and win by 20. But the one-point move off the opener shows others are convinced JMU can keep it closer.

Early James Madison vs Louisville total pick: Under 57.5 (-110)

My fair number projects closer to 54.5, so if this climbs past the key number of 58, the Under becomes even more attractive. Thus, I’m much more interested in potentially having action on this side of the game than on the spread.
 
Louisville’s defense, while erratic under DC Ron English last year, showed flashes. Blown coverages and poor tackling were common, but much of that looked like communication breakdowns. If those clean up, the defense has capable, underrated disruptors — Clev Lubin posted two sacks in the opener, with Jordan Guerad and Stanquan Clark also capable of making plays. I’m probably a bit higher on the market on this defensive unit because of those things.
 
Offensively, Louisville still needs more consistent receiving options beyond Caullin Lacy and Chris Bell. Until that develops, we’re likely to see more growing pains in the passing department. A good example came in the opener when what appeared to be a miscommunication between the receiver and QB Miller Moss aided a pick-six for Eastern Kentucky. With that in mind, I think you’ll see Louisville more than willing to hand the ball off to one of the most well-rounded backfields in the country, eating up clock in the process.
 
JMU’s defense allowed 13 sacks a year ago and could struggle to handle Louisville’s pressure. Combine that with Louisville’s run-heavy lean, and tempo should be slow enough to keep this total under the current number.

James Madison vs Louisville odds

• James Madison vs. Louisville spread: Louisville -14.5
• James Madison vs. Louisville moneyline: James Madison +440, Louisville -610
• James Madison vs. Louisville Over/Under: 56.5

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