Week 2 College Football Predictions: NCAAF Best Bets for Friday, September 5

Aug 30, 2025; Louisville, Kentucky, USA; Louisville Cardinals running back Isaac Brown (1) runs the ball against Eastern Kentucky Colonels linebacker Kaden Smith (24) during the first half at L&N Federal Credit Union Stadium.
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Sam Avellone

CFB

Long-time suffering Browns fan born and raised in the greater Cleveland, Ohio area who now resides in SEC country. University of South Carolina alum. Sports handicapper for close to 10 years with a primary focus on NCAAB while enjoying NFL, PGA, NCAAF, NBA, and Soccer. For Sam Avellone media enquiries, please email contact@pickswise.com.
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The college football season is off and running, and while there aren’t many weeknight games this week compared to Week 1, there still are a few interesting matchups to bet on Friday night ahead of Saturday’s main slate. Louisville hosts James Madison at 7:00 pm ET on ESPN2, while Northern Illinois vs Maryland kicks off from College Park at 7:30 pm ET on Big Ten Network. In the nightcap, we will see if the Boise State Broncos can bounce back from their disappointing road trip to South Florida at home on the blue turf against an FCS opponent in Eastern Washington. 

While Friday’s card doesn’t offer many options, there is one bet that stands out to me more than the rest. Here is my Friday college football best bet for Week 2.

Don’t miss our NCAAF predictions for all of the hottest games on the Week 2 slate

CFB Best Bet: Louisville Cardinals team total over 34.5 vs James Madison Dukes (-118) 

Odds available at FanDuel Sportsbook at the time of publishing. 

Last season, James Madison had one of the best defenses in the country, finishing not only top 25 in scoring and total defense, but 4th in PPA and 1st in success rate outside of garbage time. However, the Dukes lost a vast majority of their top defenders in the offseason, including many of their best run-stoppers and tacklers – which is a concern in this specific matchup.

Louisville has one of the strongest ground games in the country with sophomore running backs Issac Brown and Duke Watson, and I expect the Cardinals to utilize them early and often against an undersized James Madison front 7 at home on Friday night. Coming off a 126-yard, 2-touchdown game on just 6 carries, look for Brown to be more involved this week against this new-look Dukes defense. I wouldn’t be surprised to see him rip off multiple explosive runs of 20+ yards through massive running lanes created by an extremely experienced Louisville offensive line that should have a physical advantage over JMU’s defensive line.

A successful run game is going to open up the passing lanes for Miller Moss against this JMU secondary. Moss threw 2 picks against FCS Eastern Kentucky in Week 1, but I’m forgiving him for those interceptions because they were passes that should have been caught. In fact, neither of them were considered turnover-worthy plays by PFF. Meanwhile, he had 3 big-time throws, which he should be able to replicate on Friday night given the talent disparity between his receivers and the Dukes defensive backs.

Head Coach Jeff Brohm is an offensive specialist, and he doesn’t typically take his foot off the gas in these non-conference games against non-power conference opponents. Dating back to his first season with Purdue, Brohm’s teams have scored at least 5 touchdowns in 6 of 8 home games against these Group of 5 and FCS opponents. Look for that to remain constant this week under the lights on Friday night.

Find our full James Madison vs Louisville prediction, including a pick on the side

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