49ers vs. Seahawks Prediction, Odds, Spread, Injuries, Trends for NFL Week 1

Iain MacMillan | Sep 2, 2025

The 49ers are road favorites against the Seahawks in NFL Week 1 action. / David Gonzales-Imagn Images

The San Francisco 49ers had a nightmare season in 2024, going 6-11 one year removed from being in overtime at the Super Bowl.

Now, with a healthy lineup and a motivated locker room, the 49ers are ready to re-establish themselves as the team to beat in the NFC West. They'll attempt to do exactly that when they head to Seattle to take on the Seahawks in Week 1 action.

Let's dive into the odds and my best bet for this divisional showdown.

49ers vs. Seahawks Odds, Spread, and Total

Odds via FanDuel Sportsbook

Spread

• 49ers -2.5 (-110)
• Seahawks +2.5 (-110)

Moneyline

• 49ers -136
• Seahawks +116

Total

• OVER 43.5 (-105)
• UNDER 43.5 (-115)

49ers vs. Seahawks How to Watch

• Date: Sunday, Sept. 7
• Game Time: 4:05 pm ET
• Venue: Lumen Field
• How to Watch (TV): NBC
• 49ers Record: 0-0
• Seahawks Record: 0-0

49ers vs. Seahawks Betting Trends

• 49ers are 1-8 ATS in their last nine games
• The OVER is 4-1 in the 49ers' last five games
• 49ers are 5-2 ATS in their last seven games vs. Seahawks
• 49ers are 0-5 ATS in their last five road games
• Seahawks are 1-4 ATS in their last five games
• Seahawks are 1-6 ATS in their alst seven home games

49ers vs. Seahawks Injury Reports

49ers Injury Report

• Jauan Jennings, WR - Questionable
• Russell Gage Jr., WR - Questionable
• Jordan Watkins, WR - Questionable
• Jakob Robinson, CB - IR
• Tanner Mordecai, QB - IR

Seahawks Injury Report

• Christian Haynes, G - IR-R
• John Rhys Plumlee, WR - IR
• Rylie Mills, DT - NFI-R
• Jonathan Hankins, DT - NFI-R
• Tory Horton, WR - Questionable

49ers vs. Seahawks Key Player to Watch

• Christian McCaffrey, RB - San Francisco 49ers

The 2023 Offensive Player of the Year had a disastrous 2024 season. He missed the first half of the season with an Achilles injury, and then four games into his return, he went down with a season-ending knee injury. The 49ers' success in 2025 depends on the health of their star running back. if he can return to 2023 form, the 49ers are going to be an NFC powerhouse. If not, they'll be in trouble.

49ers vs. Seahawks Prediction and Pick

In this week's edition of the Road to 272 Bets, I broke down why I'm betting on the 49ers to win and cover as short favorites:

I'm all in on the 49ers this season. Don't let their record from last season fool you. They had the highest DVOA in NFL history amongst teams that suffered double-digit losses, and they finished second in the league in Net Yards per Play behind only the Baltimore Ravens. They were the victims of bad injury luck and poor late-game variance. Now, with a healthy lineup, I expect them to re-establish themselves as one of the best teams in the NFC.

I'm also not yet convinced Sam Darnold will be as good this season as he was for the Vikings last year. On top of that, the loss of DK Metcalf and Tyler Lockett for the Seahawks can't be understated. I have no problem backing the 49ers as small favorites.

Pick: 49ers -2.5 (-110) via FanDuel

---

Create a new FanDuel Sportsbook account, and you can get $150 in bonus bets if you win your first $5 wager. Download the FanDuel app and deposit a minimum of $5 to claim your new-user bonus today.

Odds refresh periodically and are subject to change.

If you or someone you know has a gambling problem and wants help, call 1-800-GAMBLER.

You can check out all of Iain's bets here!