College Football Week 5 Picks: Best Bets and Predictions

College football is back, baby! From now until the start of December, we will be keeping a close eye on all the action, sharing our expert analysis and betting insights every week. Stay up to date with the top picks, predictions, and betting advice for all things college football. 

Check out what bets we’re targeting with our Week 4 selections!

Where to Watch (4) LSU Tigers vs. (13) Ole Miss Rebels

• Stadium: Vaught-Hemingway Stadium
• Location: Oxford, MS
• Where to Watch: ABC
• Time: 3:30 p.m. ET
• Spread: Ole Miss -1.5 | Total: 54.5
• Moneyline: Ole Miss -118 | LSU -102 

Note: All odds are subject to change after article publication. Get the most up-to-date odds here.

The SEC is always a war of attrition, and the 2025 season is no exception. Those battles continue in Week 5, with the Ole Miss Rebels and LSU Tigers looking to bolster their respective playoff hopes. The betting market may have the Rebels out in front, but we see value in backing LSU to stun Ole Miss at home. 

Already, LSU has marquee wins over the Clemson Tigers and Florida Gators. While both teams may not be as competitive as we once thought they were, the Tigers’ dominance is a definite factor in those programs’ early-season woes. LSU held both teams to 10 points while giving up an average of 313.5 yards per game in those contests and forced a combined six turnovers. At the same time, Garrett Nussmeier and the Tigers’ offense have methodically taken care of business.

The Rebels’ wins have come in less impressive fashion. Ole Miss covered a hefty spread in the season opener, following that up with a seven-point win over Kentucky as -8.5 chalk and a 41-35 victory over unranked Arkansas at Vaught-Hemingway Stadium. 

Both teams will put up points, but the winner will be decided by which team can make the most defensive stops. In that regard, we have the utmost confidence in LSU to continue its unrelenting start to the season. We’re getting a piece of the Tigers on the moneyline.

Best Bet: LSU -102

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Where to Watch (6) Oregon Ducks vs. (3) Penn State Nittany Lions

• Stadium: Beaver Stadium
• Location: University Park, PA
• Where to Watch: NBC
• Time: 7:30 p.m. ET
• Spread: Penn State -3.5 | Total: 52.5
• Moneyline: Penn State -152 | Oregon +126

A loss from either program doesn’t dash their playoff aspirations. Still, the Oregon Ducks and Penn State Nittany Lions will be looking to assert themselves in this Big Ten clash. Oregon has looked impressive early this season, but the advantage lies in backing Penn State in this pivotal conference showdown. 

Penn State is one of the most efficient programs on both offense and defense. The Nittany Lions have a top-ten-ranked defense, limiting opponents to the ninth-fewest total yards and the third-fewest points. That defensive integrity doesn’t come at the expense of offensive productivity, as PSU is averaging 44.0 points and 437.3 yards per game this season. 

While Oregon can match those production numbers, we have concerns about its ability to travel to Beaver Stadium to secure the win. In their lone road contest this season, the Ducks gave up 313 yards of total offense to the lowly Northwestern Wildcats, falling short of the -26.5 spread in a 34-14 win. In that same game, Oregon put up 373 yards on offense, a significant departure from its 523.8-yard average. 

Two primary factors are pointing us toward the Nittany Lions in this one. First, Oregon isn’t the same team on the road, and Beaver Stadium is a notoriously challenging venue in which to succeed. Second, Penn State planned its schedule so it would be coming off a bye and fresh for this focal Week 5 tilt. Count us as one of the few bettors backing the Nittany Lions to cover at home. 

Best Bet: Penn State -3.5 (-102)

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Where to Watch Louisville Cardinals vs. Pittsburgh Panthers

• Stadium: Acrisure Stadium
• Location: Pittsburgh, PA
• Where to Watch: ESPN2
• Time: 12:00 p.m. ET
• Spread: Louisville -4.5 | Total: 57.5
• Moneyline: Louisville -182 | Pittsburgh +150

With a bevy of other show-stopping contests on the docket, it’s easy to look past the ACC battle between the Louisville Cardinals and Pittsburgh Panthers. Nevertheless, we have this game earmarked as one of the premier showdowns on the early slate. Louisville is trying to punch its way into the Top 25, but the Pittsburgh Panthers aren’t a team that will roll over and die. 

Smartly, Louisville has started its season with three contests against Group of Five and FBS teams to get its offense on its feet. Still, the Cardinals have looked somewhat unimpressive. Despite taking on lesser-than opponents, the Cards are averaging just 415.0 yards per game. Their passing attack has looked flightless, and their ground game has done just enough to keep the possession metrics modestly tilted slightly in their favor. 

Pitt was dealt a blow in The Backyard Brawl, but an overtime loss in a heated rivalry game on the road is hardly a red flag for sophomore quarterback Eli Holstein. The Louisiana native has been one of the more impressive signal callers this season, averaging 9.3 yards per pass attempt and throwing nine touchdowns in three games. While the rushing attack needs to find its footing, Desmond Reid should have no problem churning out yards against a Louisville team that has been out-gained in consecutive outings.

It’s just a matter of time before Louisville comes up short, and we’re betting the Cardinals’ descent starts versus Pitt. This has field-goal game written all over it. While some reckless bettors will land on the Panthers moneyline, we’re playing it safe and taking them to cover the spread on the other side of a key number.

Best Bet: Pittsburgh +4.5

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College Football Week 5 Picks: Best Bets and Predictions

• LSU -102
• Penn State -3.5
• Pittsburgh +4.5

There is no shortage of intrigue on this crowded Week 5 slate. We’re targeting LSU on the moneyline, with Penn State and Pittsburgh to cover their respective conference showdowns in Week 5.

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