2025 NFL picks, score predictions for every Week 4 game

Who is winning in Week 4?
NFL Picks, NFL Predictions, Week 4, Patrick Mahomes
NFL Picks, NFL Predictions, Week 4, Patrick Mahomes | Kathryn Riley/GettyImages
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New Orleans Saints (0-3) @ Buffalo Bills (3-0)

Sunday, September 28, 1:00 PM ET

This is the NFL equivalent of college teams playing the pep band the week after a primetime matchup. Get a load of this – the Buffalo Bills are opening as 16.5-point favorites at home against the New Orleans Saints.

That might be the most disrespectful opening line for an NFL team I’ve ever seen, yet it feels extremely right.

The Bills are a juggernaut, and the Saints just had their lunch money stolen before being shoved in a locker by the Seattle Seahawks. There’s really very little doubt about the Bills being able to coast to a fourth-straight win to start this season, but we’ll all have to wait to find out exactly “how” it happens.

Buffalo is not only the better and more talented team, but they’re also going to be playing this game on a bit of extended rest after playing against the Dolphins on Thursday this past week. The Saints looked as bad as many have expected them to be, and it would be shocking if they were even able to keep this one close for a couple of quarters.

Weird things happen all the time in the NFL, but you probably don’t have to worry about that if you’re a Bills fan in this one. This is all about taking care of business and coming out of the game healthy if you’re Buffalo. The intriguing thing to watch for New Orleans here might be how quickly we see Tyler Shough getting on the field. He briefly appeared against the Seahawks and perhaps this will be the ideal time to get him out there for an entire half if the Saints are in bad enough shape after the first two quarters.  

Prediction: Bills win 34-10