NCAA Football Predictions: Week 5 Opening Line Report and Picks

by Joey House - 9/22/2025

College football Week 5 opening line report Fernando Mendoza Indiana Hoosiers

As temperatures began to cool, Week 4's OLR plays were on fire. We swept the board, going a perfect 3-0. Our play on Oklahoma highlighted the usefulness of early betting, as the spread opened at the Sooners as 6-point favorites. It closed at Auburn +7, and when the Tigers fell 24-17 in Norman, Oklahoma, late bettors found themselves with a push. Michigan covered its 2.5-point spread by the hook, defeating Nebraska 30-27. Miami finished our perfect night, covering a 7.5-point spread 26-7 against in-state rival Florida.

Doc’s Sports offers college football expert picks for every game on our college football predictions page.

Double-digit Dog Outright Winners

Starting with Friday night's 19-12 Tulsa victory over Oklahoma State as a 10-point dog, there were six games where double-digit favorites lost outright. While Syracuse was the biggest dog (+17.5) to win, taking down Clemson in Death Valley, San Diego State covered their two-touchdown underdog spread by almost 50 points, slaying California 34-0.

Dead Men Walking and Their Buyouts

As of Sunday night, there haven't been firings, but there have been plenty of rumors flying around. Florida's Billy Napier has the shortest odds of being axed at +400. Saturday's 26-7 loss at Miami was a close affair until the last four minutes of the fourth quarter, when the Hurricanes scored two touchdowns. However, even though the score was tight, the game was in fact dominated by the Canes. The Gators had 141 yards of total offense and were 0-13 on 3rd down conversions. While many Florida fans question his football intelligence, he's a genius due to his buyout, which is 85% of his remaining contract, with 50% of it due within 30 days of his termination, making it difficult to move on from him.

Oklahoma State's Mike Gundy is a legend in Stillwater. He became the Cowboys' all-time passing leader in yards and touchdowns in his senior season in 1986 and has coached the four QBs that have since passed him. Gundy's 170 victories are 108 more than those of his coach, Pat Jones, who ranks second. However, the rumblings started when his 2024 squad, which was a preseason favorite to win the Big 12 title, finished 3-9 and winless in conference, and the Cowpokes missed their first bowl game since Gundy's rookie campaign in 2005. The 2025 season started with an inauspicious non-covering win against FCS UT-Martin. In the last 3 weeks, those rumblings have turned into a deafening roar, with the team getting routed by Oregon 69-3 and the aforementioned loss as a 10-point favorite to Tulsa. Even though Gundy's buyout is substantial ($15 million), the Cowboys' athletic booster program is in the top-10 in the nation and a top-50 athletic department.

Week 5

Duke vs Syracuse (+5.5/60.5) Sat., Sep 27th Noon ACC Network

Duke heads to Syracuse for an ACC matchup, arriving at 2-2 with a balanced offense averaging 34 points and 464 yards per game, mixing sharp passing at 332 yards per contest with a ground attack that controls the clock at 4.9 yards per carry. The Blue Devils have exploded in wins against lesser foes but shown resilience in close losses, while their defense racks up pressure with 10 sacks through four games to disrupt rhythms and force turnovers. Syracuse sits at 3-1 after a huge upset victory at Clemson, but lost their star quarterback to a season-ending Achilles injury in the process, forcing a backup into a pass-heavy scheme that averages 354 aerial yards per game yet struggles on the ground with just 3.3 yards per rush. Their line has crumbled under 11 sacks already, exposing the signal-caller to hurried decisions against aggressive fronts. The Orange have shown upset potential at home yet falter when protections break down, especially now with diminished leadership under center, allowing opponents to dictate tempo. This game opens with competitive exchanges amid the Carrier Dome energy, but the Blue Devils' superior balance and pressure capitalize on the quarterback change for a second-half pullaway.

Pick: Duke -5.5 and UNDER 60.5

No. 11 Indiana vs. Iowa (+7/48.5) Sat., Sep 27th 3:30 p.m. Peacock

Indiana storms into Kinnick Stadium flawless at 4-0, firing on all cylinders with an offense dropping 48 points and 512 yards per outing via a deadly blend of 345-yard passing barrages and a clock-grinding rush at 5.2 yards a pop, backed by a ferocious defense that's notched 12 sacks to torment quarterbacks and seize momentum. The Hawkeyes hobble in at 2-2, grinding out meager wins with a plodding attack that musters 28 points on 398 yards but falters hard against resilient lines, achieving a sluggish 4.1 yards per carry and an erratic passing game that's turnover-prone when blitzed, with their protection already breached for nine sacks. Iowa's lockdown defense holds foes to 18 points yet cracks under multifaceted offenses that pair ground pounds with vertical threats. Under the spotlight-grabbing helm of highly Googled Curt Cignetti, the Hoosiers are demonstrating that their prior triumphs were no mere fluke, as evidenced by the recent 63-10 thrashing of a once-top-10 Illinois squad, while finally flipping the script on decades of drubbings from fellow Big Ten powerhouses.

Pick: Indiana -7 OVER 48.5

No. 6 Oregon vs. No. 3 Penn State (-3.5/52.5) Sat., Sep 27th 7:30 p.m. NBC/Peacock

The rematch of last season's Big Ten Championship is the only Top 10 showdown on the weekend, with Oregon arriving in Happy Valley at 4-0 and boasting an offense ranked 6th in points per game (48.0), 8th in yards per game (529.7), and 3rd in scoring defense (8.0 ppg). Penn State has looked pedestrian through three wins over inferior competition, but still ranks 3rd in scoring defense (5.7 ppg), 4th in defensive yards per play (3.59), and tied for 10th in defensive yards allowed per game (224). One of the Nittany Lions' biggest edges may come from the crowd, as this will be one of Penn State's famed "White-Outs", notorious for disrupting opponent communication. James Franklin aims to shed the mocking label of "Big Game James", though Oregon's Dan Lanning has a track record of questionable in-game decisions himself. Saturday's game won't mirror the shootout from their last meeting, but the result stays the same. Grab the points now because this line is likely to close under a field goal.

Pick: Oregon +3.5 and UNDER 52.5

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Start:	September 22, 2025 @ 8:30 PM
Expert:	Raphael Esparza (VSI)
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NCAA Football Predictions: Week 5 Opening Line Report and Picks

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