The Jacksonville Jaguars hope to pick up a huge road win as they travel to face the unbeaten San Francisco 49ers in a Sunday afternoon battle. FOX has live coverage beginning at 4:05 p.m. ET.
The 49ers will welcome Brock Purdy back to the field and hope that the defense can overcome the loss of Nick Bosa. The Jaguars will need to continue playing well on defense while the offense looks to stop committing so many back-breaking penalties.
My Jaguars vs. 49ers predictions and NFL picks explain why points might be at a premium on Sunday, September 28.
Jaguars vs 49ers prediction
Jaguars vs 49ers Best bet: Under 46.5 (-110)
The Jacksonville Jaguars have a problem on offense, and that is consistently being inconsistent. They rank eighth in the league in total offense, but have a negative EPA/play. They also rank sixth in yards per rush, yet have thrown the ball the sixth-most times of any team.
Penalties are a big part of that problem. The Jaguars are racking up more than 72 penalty yards per game, the sixth-most in the NFL, while ranking in the Top 10 of most penalties per play.
But so is Trevor Lawrence’s performance, as the Jags have the second-worst passing completion rate in the NFL. And this is despite his offensive line allowing the second-fewest pressures in the league.
The good news for the Jaguars is how well the defense is playing. They’ve notched nine takeaways through three games, are holding opponents to the fourth-fewest yards per pass attempt, and are limiting teams to below 210 passing yards per game despite facing the second-highest passing rate.
San Francisco 49ers quarterback Brock Purdy will present a tougher challenge than what Bryce Young and CJ Stroud could. But he’s banged up, will be without George Kittle, and he’s going to face a system that is limiting big plays. He’s also playing behind a line that has allowed 10+ pressures in all three games.
There’s also the issue of Christian McCaffrey still looking to get going. He’s averaging just 3.4 yards per carry this season, and hasn’t topped 70 yards in a game despite already getting 52 carries. That includes just 55 yards on 13 carries against New Orleans.
The loss of Nick Bosa is a blow, but I’m not sure the 49ers will need it. Jacksonville will continue shooting itself in the foot on offense and falling behind the chains, while the 49ers will continue their struggles to score touchdowns in the red zone.
Jaguars vs 49ers same-game parlay
While McCaffrey’s rushing numbers haven’t been good, he’s doing damage in the passing game. He’s already caught 25 passes through three games, with 52+ receiving yards in all three games.
Jacksonville ranks in the Top 10 in QB pressures, and Purdy’s going to look for his safety valve early and often. Toss in the designed pass plays to get CMC involved, and he’ll top that total fairly easily.
While Travis Etienne has had a solid start to the season, he’s also benefited from his offensive line giving him the second-most yards before contact of any back in the league.
Rookie back Bhayshul Tuten has seen an uptick in carries the last two weeks and has already done a good job of forcing missed tackles. I expect he’ll see a higher share of the carries against the solid San Francisco front seven and get to at least 25 yards on the ground.
Jaguars vs 49ers SGP
- Under 46.5
- Christian McCaffrey Over 42.5 receiving yards
- Bhayshul Tuten Over 23.5 rushing yards
Our big-ticket SGP: Backs have a field day
Jacksonville has the second-best tackle rate of any defense in the NFL and has allowed the fewest yards after contact of any team. Given McCaffrey’s struggles to run the ball, it’s hard to see him suddenly breaking out against the Jags.
On the flip side, he’s already been targeted 31 times this season. That’s more than any other back in the league, and he’s coming off a game where he caught 10 passes for 88 yards against the Cardinals. With Kittle still sidelined, expect him to keep getting a high volume of passes thrown his way.
Jaguars vs 49ers SGP
- Under 46.5
- Christian McCaffrey Over 42.5 receiving yards
- Bhayshul Tuten Over 23.5 rushing yards
- Christian McCaffrey Under 72.5 rushing yards
- Christian McCaffrey Over 5.5 receptions
Jaguars vs 49ers game predictions
Jaguars vs 49ers moneyline prediction
I think San Francisco wins this game. Until Lawrence proves that he can perform consistently enough to defeat a good team late, especially on the road, I’m not betting on him doing so.
Jaguars vs 49ers spread prediction
With the Jaguars getting the hook, I’ll take them to stay within a field goal. San Francisco has won its first three games by a combined eight points, and this game should be a tight, low-scoring affair.
Jaguars vs 49ers Over/Under prediction
I’m on the Under for this game as my best bet.
Jaguars vs 49ers odds
- Spread: Jaguars +3 | 49ers -3
- Moneyline: Jaguars +155 | 49ers -177
- Over/Under: Over 45 | Under 45
More NFL picks and odds from Covers
Jaguars vs 49ers trend to know
The San Francisco 49ers have covered the 1Q Spread in 15 of their last 20 games (+10.85 Units / 47% ROI). Find more NFL betting trends for Jaguars vs. 49ers.
How to watch Jaguars vs 49ers
| Location | Levi's Stadium, Santa Clara, CA |
| Date | Sunday, September 21, 2025 |
| Kickoff | 4:05 p.m. ET |
| TV | FOX |
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