Jacksonville Jaguars vs San Francisco 49ers Prediction, Odds and Picks for Sunday, 09/28/25

The San Francisco 49ers will be hoping to remain undefeated when they host the Jacksonville Jaguars in Week 4 on Sunday afternoon. It’s almost a miracle that San Francisco is 3-0, so it feels like only a matter of time before the first loss arrives. Head coach Kyle Shanahan’s crew won by 4 over Seattle, by 5 over New Orleans and by 1 over Arizona. It’s hard to even describe how bad the Saints are, but they had the ball around midfield late in the game with a golden chance to score a touchdown and beat the 49ers. Even though that game was on the road and this one is at home, Jacksonville still presents a much tougher test than San Francisco. Things get even more difficult, too, because edge rusher Nick Bosa is out for the year with a torn ACL — joining George Kittle and Brandon Aiyuk among players who are also out. Moreover, quarterbacks Brock Purdy (shoulder/toe) and Mac Jones (knee) are questionable.

Despite being just 1 game over .500, the Jaguars have a point differential of +29. Their only loss has come by 4 points to the Bengals, which certainly isn’t a good result — but at least they bounced back from it to beat the Texans 17-10 this past weekend. Jacksonville is #5 league wide in rushing defense and it is tied for first with a +5 turnover differential. This is by no means the best team in the NFL, but there is a lot to like about head coach Liam Coen’s inaugural Jaguars squad. Look for the visitors to cover and perhaps even win outright on Sunday.

Jacksonville Jaguars vs San Francisco 49ers prediction: Jaguars +3.5 (-115) available at time of publishing. Playable at that number.

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A Jaguars vs 49ers pick that I like even more is Under 47.5. Really the only thing to like about San Francisco’s offense is Christian McCaffrey. The quarterback room is in shambles, Kittle and Aiyuk are both on the sideline and the offensive line also has issues. Jacksonville’s run defense has been stellar so far in 2025; if it can contain McCaffrey, the Niners’ offense will be thoroughly one-dimensional.

The Jaguars have mostly been getting it done with defense. They are stopping the run and forcing turnovers — a recipe for successful football. What’s concerning is that Trevor Lawrence still isn’t playing like a #1 overall pick. The Clemson product has thrown as many interceptions as touchdowns (4 apiece) so far this season. Rookie receiver Travis Hunter, the #2 selection, has not yet done anything on the offensive side of the ball (10 receptions for 76 yards). All things considered, this matchup has the makings of a defensive struggle.

Jacksonville Jaguars vs San Francisco 49ers prediction: Under 47.5 (-115) available at time of publishing. Playable to 47.

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