Louisville vs. Pittsburgh Prediction and Picks for Saturday, September 27th, 2025
ACC Football season is upon us, and we have a thrilling conference clash on Saturday afternoon between the Louisville Cardinals (3-0, 0-0 ACC) and the Pittsburgh Panthers (2-1, 0-0 ACC). We’ve got you covered with our Louisville vs. Pittsburgh prediction. Kickoff is scheduled for 12:00 ET from Acrisure Stadium in Pittsburgh, PA. Looking to win big this football season? We have the best College Football Picks to help you out!
Cardinals Stay Perfect at 3-0
This is head coach Jeff Brohm’s third season at the helm of the Louisville Cardinals football program, and he has compiled a 22-8 (12-4 ACC) mark thus far. That includes this year’s perfect 3-0 start, where Louisville has taken care of Eastern Kentucky (51-17), James Madison (28-14), and Bowling Green (40-17), most recently. Despite being a perfect 3-0 SU, the Cardinals have yet to cover a spread (0-3 ATS) this season. They’re 2-1 to the over.
It’s redshirt senior Miller Moss, a USC transfer, taking the reins of the Louisville offense this season. The signal caller has thrown for 690 yards on a 66.3% completion rate this year. He has only two touchdowns and two interceptions in the three games. WR Chris Bell is his top target, and the pass catcher has 13 receptions for 197 yards and a touchdown. RB Isaac Brown has emerged as the top rusher, gaining 248 yards and three touchdowns on 19 carries (13.1 YPC). Brown (leg) is banged up and had just one carry against Bowling Green. Duke Watson is also dealing with a lower-body injury.
- The Cardinals have a lofty win total of 9.5 (+130/-170) currently, and they’re priced at +850 to win the ACC title.
- Louisville’s offense has been strong this season, ranking 29th in scoring (34.0 PPG), while putting up 351.5 yards per game (80th).
- On the defensive side, the Cardinals are 17th this season, allowing 15.5 points per game. In terms of yardage, they’re 25th, conceding 292.0 yards per contest.
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Panthers Drop Backyard Brawl
Meanwhile, Coach Pat Narduzzi and his Pittsburgh Panthers are looking to shake off a heartbreaking loss in the Backyard Brawl on September 13th. They lost on the road to West Virginia in a 31-24 overtime contest. The Panthers sit at 2-1 overall, and they’re coming off of a bye week in week 4. Their wins are against Duquesne (61-9) and Central Michigan (45-17). Pittsburgh enters the new week at 2-1 ATS and they’ve seen two of their three games go over the total.
QB Eli Holstein is in his second year with Pittsburgh, and he’s working with second-year offensive coordinator Kade Bell. Holstein has thrown for 822 yards on a 65.9% completion rate this season, logging nine touchdowns and three picks. Top RB Desmond Reid (lower-body) is questionable for this game. He has 142 yards and a touchdown on 24 carries (5.9 YPC). If he can’t go, it’ll be Juelz Goff (84 yards, 2 TD) getting a bulk of the rushing workload. WRs Raphael Williams Jr. (245 yards, 3 TD) and Bryce Yates (143 yards, 1 TD) are Holstein’s favorite receivers so far in 2025.
- Pittsburgh’s updated win total is just 5.5 (-125/-105) games entering the new week.
- Offensively, the Panthers are scoring 34.5 points per game (27th), while averaging 406.5 yards per week (51st).
- Defensively, they are 57th in the country this year, conceding 24.0 points per game. They’re allowing 325.5 yards per contest, which is 37th.
Louisville vs. Pittsburgh Pick
Spread Pick for Louisville vs. Pittsburgh
- Pittsburgh Panthers +4.5 (-110) (5 units)
This is one of the under-the-radar games this weekend, and it’ll be a big win for the victorious school since the ACC feels wide open in 2025. With all of that being said, I’m going to take the points with Pittsburgh. I just can’t get there with laying more than a field goal’s worth of points on the road with Louisville, even though they are likely the slightly better team.
The home-field advantage is the biggest factor in this game for me. The Panthers have been very profitable at home in recent years, going 10-2 ATS in Pittsburgh. They’re also coming off of a bye week, so the extra week of prep and rest should have Coach Pat Narduzzi’s squad ready to rumble. Eli Holstein (822 yards, 9 TD, 3 INT) has looked serviceable this season and we’ve yet to see Louisville’s Miller Moss (690 yards, 2 TD, 2 INT) have an impact in 2025. I think the Panthers can keep this game within the number at home.
Over/Under Pick for Louisville vs. Pittsburgh
- Under 58.5 (-115) (5 units)
I expect to see some scoring in this game, but we have to draw the line somewhere. 58.5 points is a pretty lofty number for a conference opener between two teams with solid defenses. Louisville has been lights out defensively this year, allowing only 15.5 points per game against FBS-level opposition. Pittsburgh has conceded only 24.0 points per game in games against FBS opponents, and that number is skewed higher due to an overtime loss to West Virginia (31-24).
Furthermore, we really haven’t seen either quarterback air it out yet this season. Miller Moss only has 690 passing yards and two touchdowns in 2025. Do we think he’s just going to flip a switch and turn into a Heisman-caliber quarterback on the road? I’m willing to bet against that. This is going to be a dog fight in the ACC opener, as it has been in years past. The under is 8-3 in the last 11 meetings between the schools. I’ll gladly take the under while it’s sitting as high as 58.5 points.
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