The Seattle Seahawks are looking to take things one step further after narrowly missing the playoffs last season, while the San Francisco 49ers are coming off an injury-riddled season which saw them finish 6-11.
My 49ers vs. Seahawks predictions will explain why some personnel changes — and injuries — should make life difficult for the road team in Week 1.
Read more in my NFL picks for Sunday, September 7 ahead of kickoff at 4:05 p.m. ET on FOX.
49ers vs Seahawks prediction
49ers vs Seahawks Best bet: Seahawks moneyline (+100)
The San Francisco 49ers are coming off an uncharacteristic season on defense, ranking 22nd in weighted DVOA and just 23rd against the run. While the defensive line did a tremendous job rushing the passer, teams were able to establish the run, and that’s part of what led to a down year.
Now that several key veterans are gone, it’s anyone’s guess what happens next. San Francisco has done its job drafting some young talent up front and signing some veterans, but this is an overall shaky unit that will have a lot to prove — and so does this re-tooled secondary.
That’s where we take a look at the Seattle Seahawks and roll with Sam Darnold in a revenge spot. He’s coming off an excellent campaign where he perfected his deep ball, and while his O-line is in rebuilding mode, we won’t have to worry about a typical 49ers pass rush on Sunday.
Meanwhile, San Francisco should take a big step back on offense, with three receivers injured — including Brandon Aiyuk — and Deebo Samuel no longer with the team.
There’s plenty to like about this Seahawks offense, so I'm taking Seattle to prevail at home.
49ers vs Seahawks same-game parlay
It’s going to be a different season for both teams with some personnel changes, and I’ll kick things off by looking at the man who will likely step in to replace Aiyuk.
Ricky Pearsall finished the season strong with 18 targets over his final two games and was on the field for 67.5% of the 49ers' team snaps last year.
Pearsall should see his workload increase on Sunday, as will third-year Seattle back Zach Charbonnet, who faces a Niners team that ranked in the top 10 in receptions allowed to running backs last season.
49ers vs. Seahawks 3-leg SGP
- Seahawks moneyline
- Ricky Pearsall o3.5 receptions
- Zach Charbonnet o1.5 receptions
Our big-ticket SGP: Sam I Am
Darnold threw for 2+ touchdowns in 12 of 17 regular-season starts with the Vikings, and he enters a new-look Seattle offense that projects to pass the ball plenty.
Brian Robinson Jr. is the new man in the San Francisco backfield, and he could see some work at the goal line with Christian McCaffrey nursing an injury.
49ers vs. Seahawks 5-leg SGP
- Seahawks moneyline
- Ricky Pearsall o3.5 receptions
- Zach Charbonnet o1.5 receptions
- Sam Darnold o1.5 passing touchdowns
- Brian Robinson Jr. anytime touchdown
49ers vs Seahawks game predictions
49ers vs Seahawks moneyline prediction
The 49ers have been as heavy as -144 favorites, but now this line is drifting toward a pick'em.
Take Seattle at plus money.
49ers vs Seahawks spread prediction
The 49ers opened as 1.5-point favorites, and after hitting 2.5 early in the week, the line has come back towards the middle.
I got Seattle at +2.5, so be sure to price shop before kickoff.
49ers vs Seahawks Over/Under prediction
The total has been falling steadily, beginning at 45.5 points and coming down to 43.5 on Saturday.
I'm taking the Over at that number.
49ers vs Seahawks odds
- Spread: San Francisco -2.5 (-110) | Seattle +2.5 (-110)
- Moneyline: San Francisco -140 | Seattle +120
- Over/Under: Over 45 (-110) | Under 45 (-110)
More NFL picks and odds from Covers
49ers vs Seahawks trend to know
Seattle has covered the 4Q Spread in nine of its last 11 games (+6.75 Units / 47% ROI). Find more NFL betting trends for 49ers vs. Seahawks.
How to watch 49ers vs Seahawks
| Location | Lumen Field, Seattle, WA |
| Date | Sunday, September 7, 2025 |
| Kickoff | 4:05 p.m. ET |
| TV | FOX |
49ers vs Seahawks latest injuries
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