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Predictions, picks and odds for NFL Week 2 game

September 14, 2025
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San Francisco 49ers vs New Orleans Saints picks, odds for NFL Week 2
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NFL Overreactions Week 1

Sports Seriously’s Mackenzie Salmon overreacts to some of the best games of NFL Week 1.

Sports Seriously

The San Francisco 49ers (1-0) visit the New Orleans Saints (0-1) at Caesars Superdome in New Orleans for a Week 2 showdown, and USA TODAY’s panel of NFL experts have locked in their picks and predictions for the action. Here’s everything you need to know before kickoff on Sunday, September 14, including live updated odds and injury report news.

Saints vs. 49ers live odds, moneyline, over/under

Get the edge with our exclusive NFL betting picks

Saints vs. 49ers picks against the spread

NameWeek 1 Record ATSChristopher Bumbaca7-7-2Lorenzo Reyes7-7-2Blake Schuster7-7-2Jordan Mendoza6-8-2Jon Hoefling6-8-2Tyler Dragon5-9-2

Tyler Dragon: San Francisco 49ers (-4.5)

The 49ers got a big Week 1 win in Seattle. The loss of tight end George Kittle is huge because the team is already thin at wide receiver. Expect the 49ers to manufacture enough offense to survive.

Christopher Bumbaca: San Francisco 49ers (-4.5)

Injuries this, injuries that. Niners still have Christian McCaffrey, who looks just fine.

Jon Hoefling: San Francisco 49ers (-4.5)

The Saints have lost seven of their last eight Week 2 games. It doesn’t matter how injured this 49ers team is. They are still more talented than New Orleans.

Jordan Mendoza: San Francisco 49ers (-4.5)

Credit New Orleans looking somewhat decent in the season opener. The 49ers look like they have some kinks to work out, especially with injuries already plauging the roster. Still, San Francisco doesn’t have much trouble.

Lorenzo Reyes: San Francisco 49ers (-4.5)

I’ll back the Niners here, but, somehow, they’re already dealing with some significant injury issues. At the very least, I would wait in the week to get more clarity on how Brock Purdy’s toe and shoulder injuries are faring.

Blake Schuster: New Orleans Saints (+4.5)

Mac Jones vs. Spencer Rattler sounds like an elite college football game, not so much in the pros. Especially not with George Kittle on IR. Give me the home dogs in a game I will only watch because it’s my job.

Saints vs. 49ers updated injury report

NFL Week 2 picks, predictions odds



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