San Francisco 49ers vs Seattle Seahawks Prediction, Odds and Picks for Sunday, 09/07/25

The San Francisco 49ers were one of the biggest disappointments in the NFL last season. One year after losing in overtime to the Kansas City Chiefs in Super Bowl 58, the 49ers sunk to last place of the NFC West at 6-11. Granted, plenty of injuries contributed to San Francisco’s downfall, highlighted by RB Christian McCaffrey being limited to 4 games. QB Brock Purdy took a step back in 2024, throwing for 20 touchdowns after compiling 31 TD passes during their Super Bowl run in 2023.

The Niners head to the Pacific Northwest to face the Seattle Seahawks in the season opener for the first time since 2011. The Seahawks finished with the same record as the NFC West champion Los Angeles Rams at 10-7, but Seattle failed to qualify for the postseason. One of the biggest issues for Seattle last season was the lack of home-field advantage. The 12th Man at Lumen Field was one of the most intimidating places to visit in the NFL, but the Seahawks slumped to a 3-6 mark at home in 2024. In a bizarre twist, Seattle owned the 2nd-best road record in the league at 7-1. The Seahawks are going through a change at quarterback as Geno Smith reunited with old coach Pete Carroll in Las Vegas. Exit Smith after throwing for 4,320 yards last season and enter Sam Darnold, who came over after a successful season with the Minnesota Vikings, posting 4,319 passing yards.

The 49ers ranked 5th in the NFL in passing yards allowed per game at 192.8, but also sat 29th in the league in points allowed per contest at 25.6. Last season, the road team won each matchup between these division rivals. The Niners rolled past the Seahawks, 36-24 as 3.5-point road favorites, while Seattle escaped Santa Clara 5 weeks later with a 20-17 triumph. The Niners closed last season at 5-8 against the spread when listed as a favorite, compared to Seattle’s 5-6 ATS mark in the underdog role, which included a 1-5 ATS record as a home underdog. Before Seattle’s victory last November, San Francisco won the previous 6 meetings, including 5 by double-digits. Let’s go with the 49ers here as a short road favorite to begin 2025 on a solid note.

49ers vs Seahawks prediction: 49ers -2.5 available at time of publishing. Playable to 3.

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The 2 meetings between the 49ers and Seahawks last season saw dramatically different results as far as the total was concerned. In the first matchup at Lumen Field in Seattle, QB Brock Purdy threw 3 touchdown passes to lead the 49ers past the Seahawks 36-24. The game easily sailed over the total of 48.5 points, while marking their highest scoring output on the road. Seattle picked up revenge at Levi’s Stadium in Week 11 with a 20-17 victory. The total closed at 49 as the Over was never threatened with the teams combining for 1 first-half touchdown. QB Geno Smith scored the game-winning touchdown on a 13-yard scamper with 12 seconds remaining as Seattle finished with fewer than 300 yards of offense.

The 49ers posted a 5-2-1 Over mark away from Santa Clara last season, which included allowing at least 24 points in 6 of those games. The Seahawks struggled at home in 2024 with a 3-6 record, while cashing the Over in 4 of those games. Seattle scored more than 24 points at Lumen Field once last season, which came in the 26-20 victory in the opener against Denver. In 3 of the last 4 matchups in Seattle, the Over has hit, as the winning team scored at least 30 points three times.

QB Sam Darnold makes his Seattle debut, as he posted 268 yards and 2 touchdowns against San Francisco last season as a member of the Vikings. The 49ers were 4-0-1 to the Over on the road last season on totals closing at 45 points or fewer. Meanwhile, the Seahawks put together a 3-2 Over mark in home games of totals of 45 or less. It will be interesting to see how Darnold plays in his Seattle debut and if last season’s career numbers were a fluke. Although the numbers trend towards an Over play, both teams were solid defensively against the pass last season and Darnold will likely be a drop-off from Smith. With that in mind, the Under looks the right side to be on.

49ers vs Seahawks pick: Under 43 (-110) available at time of publishing. Playable to 42.5.

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