The Jacksonville Jaguars will head west to face the undefeated San Francisco 49ers at Levi’s Stadium on Sunday. This Week 4 matchup features two teams with winning records and injury questions at the quarterback position having a chance to impact the outcome. Before kickoff from Santa Clara, continue reading to get my Jaguars vs 49ers prediction.
Our Jaguars vs 49ers Pick
- Pick: Under 46.5
- Confidence: ★★★☆☆
Game Snapshot
- Matchup: Jacksonville Jaguars vs San Francisco 49ers
- Date & Time: Sunday, September 28, 2025, 4:05 p.m. ET
- Venue: Levi’s Stadium, Santa Clara, CA
- Broadcast: FOX
Jaguars vs 49ers Odds
| Betting Market | Odds |
|---|---|
| Spread | 49ers -3.5 |
| Moneyline | 49ers -175, Jaguars +150 |
| Total (Over/Under) | 46.5 |
Key Storylines
- Injuries Impacting the 49ers: San Francisco faces significant injury concerns, particularly on offense. Star defensive end Nick Bosa is out for the season due to a torn ACL and quarterback Mac Jones is questionable with a re-aggravated PCL injury. Tight end George Kittle and wide receiver Brandon Aiyuk are also sidelined. The Niners will have to overcome some major adversity to stay undefeated.
- Jaguars’ Defensive Strength: Jacksonville’s defense has been impressive, ranking among the top teams in points and yards allowed. Their ability to capitalize on the 49ers’ injuries could be huge in this matchup.
- Quarterback Storylines: If Mac Jones is able to play for the Niners, he would be facing his former team in this game. If he can’t play, the Niners would have to find a healthy quarterback to bring in.
Quarterback Play
Trevor Lawrence leads the Jaguars’ offense. He has thrown for 671 yards, four touchdowns, and four interceptions. While his performance has been solid, he faces a challenging test against a 49ers defense that remains dangerous despite some key injuries.
Mac Jones has stepped in as the 49ers’ starting quarterback in Brock Purdy’s absence. Jones has been efficient, completing 53 of 80 passes for four touchdowns and one interception. Jones is questionable and would have a chance to play his former team if he’s able to go.
Betting Trends & Head-to-Head
- Both teams are 2-1 against the spread this season.
- Both teams have seen two of their first three games go under their totals this season.
Jaguars vs 49ers Model Projection
- Score Projection: Jaguars 23 – 49ers 20
- Win Probability: Jaguars 52%, 49ers 48%
Final Thoughts
This game could come down to whether or not the 49ers have a healthy quarterback to rely on. If Mac Jones is unable to go, that would be three injured quarterbacks on the roster for the 49ers. That would require the Niners to find a quarterback who could actually play in Week 4 and it certainly wouldn’t be their first or second choice.
Whether or not Jones can play, I think the under is the best bet for this contest. The Jaguars are inconsistent on offense with Trevor Lawrence leading them. That and the quarterback uncertainty for San Francisco leads me to believe that this game won’t reach the total, with the winner likely scoring in the low-20s when all is said and done.
