Louisville vs. Pittsburgh Picks and Prediction, Saturday, September 27, 2025

It’s the first game of the ACC schedule on Saturday, Sept. 27. Read our Louisville Cardinals vs Pittsburgh Panthers prediction along with our other NCAAF Betting Picks! The Cardinals are 3-0, but they haven’t played very stern competition with their games coming against Group of Five opponents. But, they have secured wins in easy fashion. The Panthers are 2-1 and are coming off of their bye week. They entered the bye week after losing to rival West Virginia in overtime. Both teams will want to get off to a good start when it comes to conference and it all begins on Saturday. Kick-off time is set for Noon EST.

Louisville to make first road trip of the season

Louisville is 3-0 this season and they have scored rather easy victories to start the season. This will be their toughest test of the year when they face Pitt. The Cardinals opened the year with a 51-17 win over Eastern Kentucky. They followed with a 28-14 home victory versus James Madison, too.

In their last game, Louisville defeated Bowling Green 40-17 at home on Saturday, Sept. 20. The Falcons actually opened the scoring with a field goal before the Cardinals scored 33 straight points to seal the win. Quarterback Miller Moss threw for 316 yards on 23-for-32 passing. The touchdowns came from the rushing attack when running back Keyjuan Brown went for 84 yards on 12 carries and two touchdowns.

Moss has thrown for 690 yards and 66% of his passes. He has thrown just two touchdowns and two picks this season. Starting running back Isaac Brown rushed for just one carry against Bowling Green as he has been sidelined with a lower leg injury. It’s unclear if he will go against Pitt, but it would be a huge loss. He broke the 100-yard barrier in the first two games of the year. Duke Watson, who had 597 yards in 2024, is also dealing with a lower leg injury.

On defense, Louisville is led in tackles by Clev Lubin with 19 tackles. He also has a team-high 3.5 sacks on the season. The Cardinals have forced four turnovers through the first few weeks of the year, too.

“As we’ve gone back and looked at last year’s game, to be quite honest, we played as good as we could play,” Louisville head coach Jeff Brohm said this week. “It was a really well-executed game plan by our guys on both sides of the ball. We were able to defeat the blitz early on against Pittsburgh, which really helped us move the ball and get points. Once we got a lead, which is always important, we were in the driver’s position the rest of the way out as far as controlling the ball, making them throw the ball more than they wanted to, which really helped our defense. That’s going to be key once again: you’ve got to have a good plan to defeat all their pressures and, even when they play base defense, they’ve got a lot of guys down in the box, supporting the run and playing aggressive”

Louisville is averaging 39.7 points per game, ranking 28th in the nation. They are averaging 259 passing yards per game, placing them 44th. The Cardinals also own the 76th-ranked rush offense, going for 156 yards per game on the ground.

On defense, the Cardinals are allowing 16 points per game, which ranks 30th. They are the fourth-best passing defense, averaging 114.7 yards per game through the air. Louisville is also the 58th-ranked rush defense giving up 130 yards per game on the ground.

Louisville is 0-3 against the spread this season. They have been double-digit favorites in every game so far this year, but they have not be able to win by the allotted margin. Two of the games have finished inside 3 points of the spread. The over is 2-1 when they have played with all three of their games set at over 50 points so far.

Pitt exits Bye Week after disappointing loss to West Virginia

Pitt is 2-1 overall this season. They started their season with a big 61-9 win over city foe Duquesne. They followed it with another big win over Central Michigan. They defeated them 45-17. The Panthers suffered their first loss of the season shortly after that and they are coming off of their bye week.

In their last game, Pitt lost 31-24 to West Virginia in overtime. The Backyard Brawl is one of the best rivalry games in the sport and it produced once again. The Panthers held a 24-14 lead with 9:23 left in the game, but the Mountaineers were able to stage a comeback and force OT. Pitt couldn’t move the ball in overtime failing to score allowing West Virginia to win the game.

The Panthers went just 4-for-17 on third down while they did win the turnover battle, West Virginia had a higher time of possession. Quarterback Eli Holstein threw for 303 yards on 22-for-37 passing. He tossed a touchdown and a pick.

Holstein has thrown 822 yards and has completed 66% of his passes through the first three weeks. He’s tossed nine touchdowns and three picks in the pass oriented offense. Rahphael Williams has been the top receiver for the team with 245 receiving yards and three scores.

On defense, Pitt is led in tackles by linebacker Raheem Biles. The team has been able to get after opposing quarterbacks as they have 12 total sacks on the season. They have forced just three turnovers this season, though.

“But both sides of the ball, it comes down to execution,” Pitt head coach Pat Narduzzi said this week. “Without execution, it doesn't matter and you can't even evaluate the play. It's like, what if we would have got that block or did this. What if we would have read our keys. So it all comes down to execution, so there's nothing that you're saying after three games, ugh, this is terrible, we can't do that or, hey, this is what we are and this is what we have to do and that's it. It comes down to execution. You've got to mix it up enough offensively and defensively to get that.”

Pitt is averaging 43.3 points per game, which ranks 17th in the nation. They are the 19th-ranked passing attack with 315 yards per game through the air. The Panthers are rushing for 109 yards per game on the ground, placing them 118th.

On defense, the Panthers are allowing 19 points per game which ranks 45th in the nation. They are the 18th-ranked rush defense, giving up 83.7 yards per game on the ground. Pitt is also the 64th-ranked passing defense, allowing 202.7 yards through the air.

Pitt is 2-1 against the spread this season. They are 2-0 against the spread when they have been double-digit favorites. They have not been an underdog this year. The over is 2-1 when the Panthers have played this season, too. The over is 2-0 when they have played at home.

Louisville vs Pittsburgh Picks

Spread Pick for Louisville vs Pittsburgh

• Pitt Panthers +4.5 (5 units)

This is the first game of the season for Louisville on the road and they will go into a tough environment. They haven’t been tested yet as they have rolled through the first few weeks.  They have relied on the rushing game, but their starting running back may miss this week due to injury. The Panthers should take advantage of this with some quick strikes and deep passes. The Panthers are the 19th-ranked passing attack, and they will fling it around the field. Pitt was close to being undefeated, but an OT loss to West Virginia allowed a blemish on their record. I think the Panthers will be fresh from their bye week, along with being a home underdog; this is a good place for the Panthers.

Take Pitt to cover.

Louisville vs Pittsburgh Over/Under Pick

• Over 58.5 (5 units) 

Offense continues to be the calling card for both of these teams through the first few weeks of the season. The Cardinals are scoring nearly 40 points per game as the over has hit twice in there first three games. The over is undefeated when Pitt has played at home, too. The Panthers are scoring 43.3 points per game and as they continue to rely on the passing game, Pitt should put up points in this game.

Take the over on Saturday.