49ers vs. Seahawks Score Prediction for NFL Week 5 (Can 49ers Pull Off an Upset in NFC West Battle?)

There are multiple marquee matchups in the NFL in Week 5, but the NFC West clash between the undefeated San Francisco 49ers and the defending Super Bowl champion Seattle Seahawks may be the best one.

Seattle is favored at home in this rematch from last season’s playoffs, and it’s coming off a solid win against the Los Angeles Chargers to move to 3-1 this season.

Brock Purdy, Kyle Shanahan and the 49ers defeated a solid Denver team in Week 4 to get to 4-0, and they’ve done it despite a ton of injuries on both sides of the ball. Purdy is the No. 2 choice for the league’s MVP, and for good reason as the 49ers are No. 1 in the league in EPA/Play and yards per play on offense.

Seattle is 1-1 since Sam Darnold (glute) returned to the lineup, losing in shocking fashion on the road against Washington before handling the winless Chargers in Week 4. Can Seattle pick up a key division win against a 49ers team that has already beaten the Los Angeles Rams and Arizona Cardinals in 2026?

All season long, the SI Betting team is using the latest odds to predict the final score of each matchup, which should help bettors make a call on spread, moneyline and total bets for Sunday. On top of that, I’m hoping to get a few final scores exactly correct throughout the NFL season, a fun thing to root for while watching the action each week.

This may be the game of the week, but who wins? I think we could see an upset in this NFC West showdown.

49ers vs. Seahawks Odds, Spread and Total

Odds via DraftKings Sportsbook

Spread

49ers +2.5 (+102)
Seahawks -2.5 (-122)

Moneyline

49ers: +130
Seahawks: -155

Total

46.5 (Over -115/Under -105)

This spread has moved back and forth between 2.5 and 3, and it’s currently set at 2.5 (though San Fran is set at plus money to cover) in the latest odds. Both of these teams are prime to make the playoffs in 2026, but San Fran is a perfect 4-0 and is an underdog for just the second time in 2026.

49ers vs. Seahawks Score Prediction

This week, SI Betting’s Iain MacMillan continued his Road to 272, where he picks every game, every week through the NFL season. In this game, he’s taking the points with San Francisco:

In my opinion, the San Francisco 49ers have been the best team in the NFL through the first four weeks. They lead the league in DVOA, Net Yards per Play, EPA per Play, and success rate. To be fair, two of their four games have been against the Dolphins and the Cardinals, and now they have some injury issues to deal with heading into Week 5, in a tough game in Seattle.

With that being said, if you're going to give me more than a field goal's worth of points on who I think is the best team in the NFL, I'm going to take that bet 10 times out of 10.

The Seahawks continue to be exactly the team they've been dating back to last season, but it's too many points for me to lay in a game that I think is a true coin flip.

I don’t want to start a quarterback controversy – because there isn’t one – but the Seattle offense hasn’t looked much better with Sam Darnold under center over Drew Lock the last two weeks. Seattle’s defense is elite, but the 49ers (No. 1 in EPA/Play) are a much more even match than anyone the Seahawks have faced in 2026.

I agree with MacMillan that this game should be a toss up, and I love the plus-money value on the 49ers to win outright and start 5-0. San Francisco’s offense has been too good – even with players out of the lineup – to pass up in this spot.

Final Score Prediction: 49ers 26, Seahawks 23

Odds refresh periodically and are subject to change.

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