Week 5 College Football Predictions: Picks Against the Spread for Every Big Game Today

• Get my best Week 5 college football against the spread picks for every big game today
• Expert CFB Week 5 ATS picks feature home dogs, road favorites, and ranked matchups
• Read below for full Week 5 college football picks against the spread for Sept. 27

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Week 5 delivers one of the best slates of the season with five ranked matchups and tight spreads across the board. The value in today’s college football predictions and spread picks is exceptional, with several lines moving significantly throughout the week.

USC is laying 6.5 points at Illinois, and the Trojans’ explosive offense gets a perfect matchup against a reeling Illini defense. Washington’s getting 8.5 at home against top-ranked Ohio State, which feels like too many points for an undefeated team in that environment.

We’ve also got ranked showdowns with LSU at Ole Miss as just 2.5-point dogs, Alabama getting 2.5 at Georgia, and Oregon catching 3.5 at Penn State. These tight lines create opportunities for smart money. My analysis incorporates advanced metrics from Pro Football Focus to identify the key edges.

Here are my best college football predictions for today’s big Week 5 games, with spread picks that offer excellent value.

College Football Picks Against the Spread Week 5

Odds as of September 27, 2025, at ESPN BET. Shop our top recommended college football betting apps for the best Week 5 prices.

CFB ATS Picks #1: USC -6.5 at Illinois

Illinois got embarrassed last week, losing 63-10 to Indiana. That was the sixth-largest loss ever by an AP Top 10 team. Now they face another explosive offense without their star slot corner Xavier Scott, who’s out with a lower leg injury.

A ZESTY 40-yard TD to Makai Lemon 🍋@uscfb pic.twitter.com/VeurqXpEPN

— FOX College Football (@CFBONFOX) September 21, 2025

The Illini have major protection issues. PFF graded their pass blocking at just 42.8 with a 40% pressure rate against Duke and Indiana. Luke Altmyer struggles against ranked teams, completing just 59.9% with a 119.8 passer rating compared to 64.6% and 152.2 against unranked opponents.

Illinois runs man coverage at the third-highest rate nationally and blitzes at the second-highest rate in the Power Four. Indiana exposed this aggressive approach for 0.788 EPA per pass. Lincoln Riley will have answers ready after watching that film.

• Pick: USC -6.5 (-125)

CFB ATS Picks #2: Washington +8.5 vs Ohio State

Julian Sayin makes his first road start at one of college football’s toughest venues. Washington’s 22-0 at home under Jedd Fisch and Husky Stadium gets loud. The Buckeyes will need silent counts all game, which limits their offensive effectiveness.

Demond Williams has been excellent for Washington, completing 73.5% of his passes with six touchdowns and zero picks. He’s also rushed for 220 yards on 34 carries. Ohio State hasn’t faced a dual-threat quarterback like this yet.

Washington QB Demond Williams Jr vs Washington State:

🟣 16/19
🟣 386 Total YDS
🟣 5 Total TDS
🟣 0 INTS@UW_Football pic.twitter.com/FGxOIifSQP

— PFF College (@PFF_College) September 21, 2025

The line opened at Ohio State -14 and dropped all the way to -8.5. That’s sharp money recognizing value. Washington is averaging 55.7 points per game and has the nation’s most efficient offense at 0.494 EPA per play.

Ryan Day’s teams have struggled in tough road spots. They lost at Oregon in 2021 and had close calls elsewhere. This Washington team has better rushing numbers than that Oregon squad, ranking second in EPA per run.

• Pick: Washington +8.5 (-110)

CFB ATS Picks #3: Ole Miss -2.5 vs LSU

Trinidad Chambliss has been electric for Ole Miss if he starts. The Division II transfer threw for 719 yards and four touchdowns while rushing for 195 yards and two scores. Multiple coaches have compared him to Kyler Murray per PFF’s analysis.

LSU’s ground game is compromised. Caden Durham is doubtful with an ankle injury, leaving them averaging just 116.8 rushing yards per game – 111th nationally. Without Durham’s 213 yards, they’ll rely on inexperienced backs against a solid Ole Miss front.

Sources: LSU leading rusher Caden Durham is considered doubtful for the game at Ole Miss. He’s dealing with an ankle injury from the SE Louisiana game last week and is unlikely to play. pic.twitter.com/G4LXU6HIcQ

— Pete Thamel (@PeteThamel) September 26, 2025

Lane Kiffin owns Brian Kelly in Oxford. The Rebels put up 707 total yards in last year’s 55-49 home win over LSU. Kiffin’s teams are 17-3 in their last 18 home games and average 44.8 points at home this season.

Garrett Nussmeier has been dealing with an undisclosed injury for weeks. He’s thrown just six touchdowns in four games, and LSU has scored 23 or fewer points in three straight FBS games. That won’t cut it against this Ole Miss offense.

• Pick: Ole Miss -2.5 (-105)

CFB ATS Picks #4: Alabama +2.5 vs Georgia

Georgia’s pass rush has been historically bad this season. PFF ranks them 125th nationally in pass rush grade with just three sacks all year – none from defensive linemen. Ty Simpson has the fifth-best clean pocket passing grade in the country. He’ll have time.

Gunner Stockton struggles under pressure with a 40.2 passing grade when pressured per PFF, ranking 104th nationally. Alabama generates pressure through coverage rather than pure rush, with the second-best pressure rate at 47% despite an average pass rush.

BACK ✌️ BACK@londonsimmons51

📺: ABC pic.twitter.com/GeYxk3Kur8

— Alabama Football (@AlabamaFTBL) September 13, 2025

The line moved from Georgia -4.5 to -2.5, indicating respect money on Alabama. The Tide are 4-1 ATS versus Georgia since 2020 and 7-3 ATS as underdogs since 2008. They know how to play with house money.

Alabama gets back Tim Keenan and Jam Miller, two key contributors who haven’t played this season. After losing to Florida State, this is a must-win for their playoff hopes. Desperation often leads to elevated performance.

• Pick: Alabama +2.5 (-110)

CFB Spread Picks #5: Oregon +3.5 at Penn State

Oregon’s offensive line is the best in college football, according to PFF. They rank first in pass blocking grade and second in pressure rate allowed. Dante Moore has been sacked just once all season, and he’s completing 75% of his passes with 11 touchdowns.

Penn State’s offense has major concerns despite playing Nevada, FIU, and Villanova. They rank 65th in EPA per pass and 75th in yards per pass. Drew Allar grades just 68.6 per PFF – 101st nationally – with a 21% uncatchable pass rate.

James Franklin is 4-19 against AP Top 10 teams at Penn State. That’s not a typo. He’s won just four times in 23 tries against elite competition. Dan Lanning already beat Penn State once in the Big Ten Championship Game.

If Oregon’s elite offensive line neutralizes Penn State’s seventh-ranked pass rush, Moore will pick apart this secondary. The Nittany Lions ran for nine yards per carry against Oregon last year and still lost. The passing game decides this one.

• Pick: Oregon +3.5 (-110)

Brady’s 2025 CFB ATS Picks Record: 6-3 (+2.5 units)