Wake Forest vs. #16 Louisville Prediction, Spread, NCAAF Picks – Saturday, September 26

Week 4 of the college football season features a polarizing ACC matchup between Wake Forest and #16 Louisville on Saturday, September 26, at 12:00 p.m. ET on ESPN. Louisville is a 13.5-point home favorite and returns a 1.16x payout with a win, via PrizePicks.

Louisville has begun the season 2-1 and is fresh off a 41-31 win over then-#16 SMU last week. Meanwhile, Wake Forest is also 2-1 and most recently gave #6 Miami all it could handle in a 33-20 loss.

Below, we’ll break down our Wake Forest vs. Louisville prediction and picks for Saturday afternoon's game, including the spread, over/under, and player projections for PrizePicks.

Make your Wake Forest vs. Louisville picks on PrizePicks now!

{{cfb_offer_banner="/style-system/ui-components-playbook"}}

Wake Forest vs. #16 Louisville Prediction, Spread, Over/Under – Saturday, September 26

Since taking over the Louisville program, head coach Jeff Brohm has led the Cardinals to 9+ win seasons in each of the last three campaigns. However, the Cardinals have finished no higher than second place in the ACC during that span.

Louisville has been tested early in the 2026 season, starting with a hard-fought 41-38 loss to then-#9 Ole Miss, which is now up to #4 in the AP Top 25 Poll. Additionally, Louisville came away with a 59-13 win against Villanova before toppling SMU.

The Cardinals are led by QB Lincoln Kienholz, who is a full-time starter for the first time after spending three seasons at Ohio State. Kienholz played sparingly with the Buckeyes but has completed 65.8% of his passes for 816 yards and 6 TDs in three games in 2026.

Most recently, Kienholz went 14 of 23 for 177 yards and 2 TDs vs. the Mustangs while rushing for 42 yards and a score. 

While Louisville is impressive through the air, the team’s rushing attack is extremely dangerous. The dynamic duo of RB Keyjuan Brown (12.8 yards per carry) and RB Isaac Brown (4.2 yards per carry) has combined to rush for 395 yards and 3 TDs this season. Keyjuan Brown has tallied 0.85 EPA/rush, which ranks second nationally.

Meanwhile, Wake Forest beat Akron and Purdue in its first two contests. The Demon Deacons did ultimately fall short against the Hurricanes last Friday but put together an admirable performance.

Wake Forest trailed 31-7 midway through the third quarter before the offense got the Demon Deacons back into the contest. QB Gio Lopez tossed second-half TDs to WR Carlos Hernandez and WR Jack Foley to cut the deficit to 31-20.

However, the Hurricanes made enough plays to fluster the Demon Deacons’ offense over the final 15 minutes.

Lopez popped up on the ACC injury report for Saturday’s game and is listed as questionable with an undisclosed injury. The former North Carolina QB had played through a hip issue against Purdue earlier this month.

The veteran QB has excelled leading the Wake Forest offense, completing 62.9% of his passes for 887 yards and 7 TDs. Lopez took advantage of Miami being without its top two CBs last week, completing 29 of 46 passes for 312 yards and 3 TDs. 

Wake Forest has tallied a 0.30 EPA/play offensively, which ranks 15th in the nation, per Game on Paper.

Wake Forest vs. Louisville Spread, Over/Under – Saturday, September 26

Louisville enters Saturday’s game as a 13.5-point favorite against Wake Forest, via PrizePicks.

Here are the full payouts for Wake Forest vs. Louisville, including winner payouts, the spread, and the over/under.

Make your Wake Forest vs. Louisville prediction on the over/under on PrizePicks.

PrizePicks data is live at the time of writing and is subject to change.

Wake Forest vs. Louisville Prediction on Over/Under – 9/26/26

Here are the key game stats and trends behind our Wake Forest vs. Louisville prediction on the over/under for the Saturday, September 26 matchup.

• The over is 3-0 in Louisville’s three games, while the over is 2-1 in Wake Forest’s contests.
• Louisville has allowed a 0.15 EPA/pass this season, which ranks 84th in the nation (39th percentile).
• The Cardinals also yield a 0.21 EPA per play on early downs, ranking 114th (17th percentile). Meanwhile, the Demon Deacons have excelled on early downs, tallying 0.29 EPA/play in those situations (90th percentile).
• With QB Gio Lopez at the helm, the Wake Forest offense has thrived, averaging 297.7 passing yards per game (fifth in the ACC). The Demon Deacons have also posted a 0.37 EPA/pass (86th percentile nationally).
• Louisville has failed to get pressure on the QB in its first three games, recording just 3 sacks (second-fewest in the ACC).
• Wake Forest has also struggled defensively at times, allowing the third-most PPG (28.3) in the ACC. 
• The Demon Deacons have been vulnerable to the ground attack, allowing a 0.22 EPA/rush (20th percentile). That could be a problem against the Cardinals, who are averaging 6.0 yards per carry as a team.
• Wake Forest allows its opponents to convert 47.6% of third- and fourth-down opportunities (36th percentile).

Lock in your Wake Forest vs. Louisville prediction on PrizePicks before kickoff.

Wake Forest vs. Louisville Picks, Player Stats for PrizePicks: 9/26/26

Here are the top Wake Forest vs. Louisville picks to target on Saturday, September 26. Today’s college football picks for PrizePicks include WR Carlos Hernandez and QB Lincoln Kienholz.

Wake Forest WR Carlos Hernandez vs. Louisville: 76.5 Receiving Yards

• Hernandez has registered at least 88 receiving yards in two of his three games in 2026.
• The Wake Forest star ranks second among pass catchers in receiving yards (322) and third in receptions (21).
• Hernandez has recorded a 25.02 EPA/play, which ranks third in the nation behind only Rutgers WR KJ Duff (43.69) and Oregon State WR Jesse Legree (34.92).
• The senior WR is tied for fourth nationally in total targets (30).

Add Carlos Hernandez + Wake Forest to cover the spread on PrizePicks.

{{cfb_offer_banner="/style-system/ui-components-playbook"}}

Louisville QB Lincoln Kienholz vs. Wake Forest: 244.5 Pass Yards

• Kienholz has thrown for 300+ yards in two of his three games.
• The Louisville signal-caller has posted a 0.34 EPA/dropback this season, ranking 26th among QBs nationally.
• Kienholz has tallied 9.13 yards/dropback, which ranks 14th among QBs in the country. 
• Wake Forest is surrendering 235.0 passing yards per game, which is the fourth-most in the ACC this season.

Add Lincoln Kienholz + Louisville to cover the spread on PrizePicks.

Make Wake Forest vs. Louisville Picks on PrizePicks

ACC play continues with Louisville hosting Wake Forest in Week 4 of the college football season. The Cardinals and Demon Deacons haven’t had trouble scoring to start the season, so there could be plenty of points on the board in Saturday afternoon’s matchup. 

Don’t wait until kickoff — make your Wake Forest vs. Louisville picks on PrizePicks now and earn real money if you’re right.

Pick college football players, predict More or Less on their stats, and cash in if you’re right. With Team Picks, you can make predictions on college football game winners, spreads, and over/unders, now available in 36 states.

Stay locked in on Playbook for college football predictions, picks, and news every day all the way through the 2026 College Football Playoff.