Jacksonville Jaguars vs San Francisco 49ers Prediction, 9/28/2025 NFL Picks, Best Bets & Odds Week 4

Game: Jacksonville Jaguars vs San Francisco 49ers

Date: Sunday, September 28, 2025

Location: Levi's Stadium in Santa Clara, CA

TV: FOX

Odds-Point Spread: 49ers (-3.5)

Total-Over-Under: 47

The Jacksonville Jaguars (2-1) are headed to Levi's Stadium on Sunday where they will compete against the San Francisco 49ers (3-0). San Francisco is 3.5-point favorites. The total is set at 47.

The Jacksonville Jaguars step onto the field holding a record of 2-1 for this campaign. The last time they stepped on the gridiron, the Jaguars faced off with the Houston Texans and walked away with a win by a score of 17-10. Trevor Lawrence finished 20-40 with 222 yards passing. He had a QB rating of 56.5 and walked away from the game with 1 interception. Travis Etienne was the rushing leader for the Jaguars with 16 attempts for 56 yards (3.5 yards per carry). Brenton Strange left with an average of 10.2 yards per catch by totaling 61 yards on 6 receptions. The Jacksonville Jaguars ran the ball a total of 24 times and totaled 86 yds, which earned them an average of 3.6 yards per tote. For the game, they ran 64 plays which gave them 291 yards. Jacksonville conceded 25 pass completions on 38 tries for 184 yards, and a completion percentage of 65.8%. Against the rush, the Jaguars gave up 87 yards on 19 attempts, which is 4.6 yards per rush allowed.

The Jaguars have amassed 1,069 yards this year. Jacksonville has attained 34 first downs as a team, and they have been hurt by 26 infractions for 218 yds. If you look at getting in the endzone, Jacksonville has recorded 4 passing touchdowns and 3 touchdowns via the ground. They have turned the ball over 4 different times. Offensively, they are sitting at 141.7 rushing yds which ranks them 5th in the league. Regarding scoring, the AFC representatives are sitting at 23.3 PPG.

The Jaguars sit 6th in the league when talking about their defensive prowess, granting 17.0 points per contest. They are allowing 4.1 yards per run and 82.7 rush yards per contest for the season. If you're looking at yards via the pass, the Jaguars have conceded 628 yards, which is 16th in the league. They have allowed 209.3 total yards per contest through the air, and are giving up a completion percentage of 60.2%. In total, they are yielding 292.0 total yards per contest, which ranks them at 10th in the NFL. They have allowed 5 touchdowns via the pass, as well as 1 touchdown on the ground. Overall, they have surrendered 248 yards via the ground game in 3 outings over the course of this season.

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The 49ers head into this matchup 3-0 for the season. In their last game, the 49ers walked away with a victory by a final of 16-15 when they played the Arizona Cardinals. Mac Jones (1 touchdown) ended the contest with 284 yds on 27-41 through the air while his QB rating was 83.8. He tossed 1 interception and his average yds per pass attempt was 6.9 yards. Christian McCaffrey ran the football 17 times for 52 yds, ending the game with 3.1 yards per attempt for San Francisco. Ricky Pearsall was one of the featured targets for the 49ers, hauling in 8 throws for 117 yards (14.6 yards per reception). San Francisco ended up running for 3.7 yards per attempt, finishing with a total of 73 yards on 20 carries. The 49ers finished the contest with a total of 355 yards on 61 plays (5.8 yards per play). The 49ers pass defense conceded a completion percentage of 62.9%, surrendering 154 yds on 22 for 35 passing. San Francisco surrendered 28 run attempts for 106 yards (3.8 yds per rush).

If you look at the points being put on the board, the 49ers currently rank 23rd in pro football, by tallying 19.7 points per game. Over the course of this season, the 49ers sit at 814 yards via the pass and are sitting at 271.3 yards via the pass per contest, which ranks them at 1st in football. They average 89.7 rush yards per contest, and have run for 269 total yards. The San Francisco 49ers maintain an average of 361.0 yards per outing, which has them sitting 7th in the league. The San Francisco offense has granted 170 yards on 19 penalties, which is good for 21st in professional football when analyzing helping out the other team. They have allowed 3 picks while allowing 1 fumble, and have recorded 44 1st downs.

They have surrendered 4 touchdowns through the air as well as 162.0 passing yds per game, which ranks them 5th in football. San Francisco has surrendered a total of 311 rushing yds (103.7 yds per game), in addition to 1 touchdown on the ground so far this year. The D has a total of 3 turnovers on the year. On the whole, they have conceded 49 pts. The 49ers defense has participated in 181 plays from scrimmage, which ranks them 14th in the league. The 49ers are surrendering 16.3 PPG, which ranks them at 3rd in football.

Who will win tonight's Jaguars-49ers NFL game against the spread?

Guy's Pick: Take the Jaguars +3.5

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