by Rod Pearson
Friday, Sep 26, 2025
Game Time: 4:05 pm ET, Sunday, September 28, 2025
Venue: Levi's Stadium, Santa Clara, CA
Where to Watch: FOX
Opening Odds at USA Sportsbooks
DraftKings: Point Spread: Jaguars +3.5, 49ers -3.5; Over/Under: 46.5 points
Bet365: Point Spread: Jaguars +3.5, 49ers -3.5; Over/Under: 47 points
BetMGM: Point Spread: Jaguars +3.5, 49ers -3.5; Over/Under: 47 points
Season Record
Jacksonville Jaguars: 2-1 (2nd place, AFC South)
San Francisco 49ers: 3-0 (1st place, NFC West)
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Recent Form
Jacksonville Jaguars: won their last game at home against the Houston Texans 17-10.
San Francisco 49ers: won their last game at home against the Arizona Cardinals 16-15.
Jacksonville Jaguars vs San Francisco 49ers Preview and Analysis
The Jaguars are entering this game with a 2-1 record overall and they have a 1-0 record in their divisional games too. They are 2-0 in their home games, 0-1 in their road games, and they are also 0-0 in their neutral site games this season, but they will be on the road for this game. They won their last game against the Houston Texans 17-10. Trevor Lawrence was the starting QB and he completed 20/40 passes for 222 passing yards, 0 touchdowns, and 1 interception. Travis Etienne Jr. led the team in rushing yards with 56 and 1 TD. Brenton Strange led the receivers with 61 receiving yards on 6 receptions. Tyson Campbell led the defense in that game with 7 solo tackles and 0 assisted tackles while Travon Walker led the defense in sacks with 1. Jourdan Lewis and Antonio Johnson each came away with 1 interception for them in that one.
The 49ers are entering this game with a 3-0 record overall and they have a 2-0 record in their divisional games too. They are 1-0 in their home games, 2-0 in their road games, and they are also 0-0 in their neutral site games this season, but they will be at home for this game. They won their last game against the Arizona Cardinals 16-15. Mac Jones was the starting QB and he completed 27/41 passes for 284 passing yards, 1 touchdown, and 1 interception. Christian McCaffrey led the team in rushing yards with 52. Ricky Pearsall led the receivers with 117 receiving yards on 8 receptions. Fred Warner led the defense in that game with 5 solo tackles and 6 assisted tackles while Bryce Huff led the defense in sacks with 1. No one on the defense came away with an interception for them in that one.
Jaguars vs 49ers Prediction
The current betting odds have the 49ers listed as a 3.5 point favorite in this game according to Draftkings Sportsbook. The 49ers have looked great in their games this season with their 3-0 record overall which has them right at the top of the NFC West. They have been winning in some tight games, but they find ways to get those wins and their defense has looked great to open up the season. Meanwhile, the Jaguars have looked good in their games this season with their 2-1 record overall. Their defense has also looked great in their 3 games to open up the season, but they have faced some much weaker offenses too. They are off a tough divisional win against the Texans 17-10, but that Texans offense hasn't done much this season. Their defense didn't look great against a backup Bengals QB either, and this is a tough travel spot for them to go across the country. The 49ers have more stability with their head coach and great defense, and they should be getting healthier for this game too. Brock Purdy could be back for the 49ers here and this offense is due for a break out game with the talent they have. The 49ers will continue to roll in this game with the much better defense and they are the better team overall too. The best way to place a bet here is on the 49ers to cover the spread in this game.
Jaguars 49ers Prediction: Our NFL Pick for Sunday, September 28, 2025 (4:05 pm ET start time) is 49ers 27 Jaguars 17.
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NFL Betting Trends
Jacksonville Jaguars: 7-4 ATS as an underdog of 3.5 to 9.5 points. 7-4 ATS in non-conference games. 9-5 ATS when playing against a team with a winning record. 6-3 OVER in a road game where the total is between 42.5 and 49 points. 10-5 OVER after playing a game at home.
San Francisco 49ers: 7-13 ATS in home games. 5-11 ATS as a favorite of 3.5 to 9.5 points. 1-5 ATS after a win by 6 or less points. 11-5 OVER as a favorite of 3.5 to 9.5 points. 9-3 OVER after playing a division game.
Key Injuries
Jacksonville Jaguars: E. Cleveland (OG) Injured - Ankle. P. Mekari (OG) Injured - Elbow. D. Brown (WR) Injured - Shoulder. B. Thomas Jr. (WR) Injured - Wrist. W. Milum (OG) Injured - Knee. B. Tuten (RB) Injured - Shoulder.
San Francisco 49ers: M. Williams (DL) Injured - Wrist. T. Williams (OT) Injured - NIR-Rest. C. McCaffrey (RB) Injured - NIR-Rest. R. Pearsall (WR) Injured - Knee. B. Purdy (QB) Injured - Shoulder. K. Davis (DL) Injured - Ankle. J. Watkins (WR) Injured - Calf. M. Jones (QB) Injured - Knee. C. West (DL) Injured - Thumb. D. Lenoir (CB) Injured - Illness. C. Colby (OG) Injured - Groin. R. Green (CB) Injured - Neck. Y. Gross-Matos (DL) Injured - Knee. J. Jennings (WR) Injured - Ankle.
Notable Quotes
“We're not going to get bullied. I feel like that's what they want to do. I'm not saying that's wrong, but that's their mindset and it's not going to happen to this team. It was fun to be able to punch back and stand up in those moments, where it's like, ‘All right, you want to throw that punch? We’re here.'” - Trevor Lawrence after their win against the Texans in their last game.
“I failed a lot in that situation, to be honest, in the NFL. I just knew the guys had my back and like we talked about on the sidelines, go out there and rip it.” - Mac Jones after their win against the Cardinals in their last game.
Starting Lineups
Jacksonville Jaguars
WR Thomas Jr., Brian
WR Washington, Parker
WR Hunter, Travis
TE Strange, Brenton
QB Lawrence, Trevor
RB Etienne Jr., Travis
San Francisco 49ers
WR BRobinson, Demarcus
WR Pearsall, Ricky
WR Moore, Skyy
TE Tonges, Jake
QB Purdy, Brock
RB McCaffrey, Christian
FB Juszczyk, Kyle
Statistical Leaders
Jacksonville Jaguars
Passing: Trevor Lawrence (671)
Rushing: Travis Etienne Jr. (270)
Receiving: Brenton Strange (137)
Touchdowns: Travis Etienne Jr. (2)
San Francisco 49ers
Passing: Mac Jones (563)
Rushing: Christian McCaffrey (176)
Receiving: Ricky Pearsall (281)
Touchdowns: George Kittle (1)
Coaches:
Jacksonville Jaguars: Liam Coen (1st season)
San Francisco 49ers: Kyle Shanahan (9th season)
Rod Pearson
About the Author:
Rod Pearson has been a rabid sports fan his entire life. He grew up in Ontario, and was skilled in both hockey and baseball, and pitched in an elite baseball league for many years. In 2022, Rod decided to hang up his glove, so that he could write about the sports he loves -- but from a gambling perspective. Join Rod every day as he breaks down the games to find the best betting value.
