Don’t sleep on what could be one of the more intriguing matchups in Week 4 of the NFL when the surprising Jacksonville Jaguars face the unbeaten San Francisco 49ers.
Liam Coen has the Jaguars playing better than expected, behind a ball-hawking defense and strong rushing attack. The 49ers are somehow unbeaten despite multiple close games and a plethora of injuries.
We dive into our early leans with Jaguars vs. 49ers predictions and NFL picks on Sunday, September 28.
Jaguars vs 49ers predictions
Here are our early thoughts on the spread and total for this week’s game. We will have a full game preview (with a best bet and SGP) later in the week.
Early Jaguars vs 49ers spread pick: Jaguars +3.5
The fact that this spread has shifted to 3.5 has me taking the Jacksonville Jaguars to cover. That hook is extremely important, especially given how banged up the San Francisco 49ers are right now.
Brock Purdy is set to return at quarterback this weekend after missing two games, provided he gets through practice this week. But the 49ers may not have a choice, after Mac Jones injured his knee.
San Francisco now must also cope without Nick Bosa, who tore his ACL and will miss the rest of the season. That gives Jacksonville a big advantage, especially with how surprisingly well they’re handling pass rushers this season.
A big reason for that is Liam Coen helping with his play-calling. Trevor Lawrence went 14 of 20 on passes that were less than 10 yards downfield against the Texans. He’s being asked to manage games while the Jaguars find success with the ground game.
But it’s the Jacksonville defense that has everyone shocked. The Jaguars lead the NFL in takeaways, and the worst secondary in the NFL last season leads the league this year with an interception rate near 6%. That said, they can be run on, and CMC will do just that.
The 49ers have won their first three games by a combined 10 points. I expect we’ll see another close one here.
Early Jaguars vs 49ers total pick: Under 46.5
I love the Under in this game, given how much Jacksonville has struggled to put points on the board.
A big reason for that continues to be penalties. The Jaguars rank 24th in penalties per offensive snap, and 27th in penalty yardage per game. That’s why despite being ranked eight in total offense, they’re scoring only 23.3 points per game.
That won’t work against a San Francisco defense ranked third in scoring, fourth in yards allowed, and fifth in yards allowed per snap. Even without Bosa, the 49ers are going to cause problems for Jacksonville and will likely force Lawrence to throw downfield a bit more.
The other reason I am bullish on the Under is the fact the 49ers rank 25th in points per play. A big reason for that is the 3.3 yards per carry, something you’d not expect with Christian McCaffrey in the backfield.
But he’s yet to top 180 rushing yards through three games and 52 carries. That will put some pressure on Purdy, who threw two picks to go with his two touchdowns in the opener.
Jacksonville is also having a lot of issues with dropped passes. Brian Thomas Jr. has been targeted on 28.8% of his routes, but he’s got as many catches as he does drops—with seven of each.
This game doesn’t have the feel of a shootout, and I won’t be surprised if this total drops before the weekend. Two of San Francisco’s games have failed to go past 31 points, and we will probably see a similar outcome here.
Jaguars vs 49ers odds
- Jaguars vs. 49ers spread: 49ers -3.5 (-102)
- Jaguars vs. 49ers moneyline: Jaguars +142, 49ers -168
- Jaguars vs. 49ers Over/Under: 46.5
How to watch Jaguars vs 49ers
- Jaguars vs. 49ers matchup
- Date: Sunday, September 28, 2025, 4:05 p.m. ET
- City: Santa Clara
- Venue: Levi's Stadium
- TV: FOX
Odds are correct at the time of publishing and are subject to change.
Not intended for use in MA.
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