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Jacksonville Jaguars vs San Francisco 49ers picks, odds for NFL Week 4

September 22, 2025
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NFL Week 3 overreactions

USA Today’s Lorenzo Reyes breaks down the biggest NFL storylines from Week 3.

Sports Seriously

The Jacksonville Jaguars and San Francisco 49ers play on Sunday, Sept. 28, at the 49ers’ Levi’s Stadium in a game on the NFL Week 4 schedule.

Which team will win the NFL Week 4 game?

Check out these NFL Week 4 picks and NFL Week 4 predictions for the game, which can be seen at 1:05 p.m. MST on FOX (stream with FUBO).

The 49ers are a 3.5-point favorite over the Jaguars in NFL Week 4 odds for the game, courtesy of BetMGM Sportsbook.

San Francisco is -190 on the moneyline, while Jacksonville is +155. The over/under (point total) is set at 46.5 points.

Watch Jaguars at 49ers live on FUBO (free trial)

Jeremy Cluff writes: “The 49ers have outscored their opponents by just 10 points in their 3-0 start. We expect another close game in this one, with a close San Francisco win. This team just finds ways to win, even amid a lot of injuries. Expect some huge Christian McCaffrey plays to seal the victory.”

NFL Week 4 picks, predictions: Who will win Jaguars vs 49ers, other pivotal games this week?

Bookies.com: Bet the 49ers to cover vs Jaguars

Bill Speros writes: “The Mac Jones Revenge Tour gets a crack at one of his former teams when the 49ers play host to Jacksonville. Mac is 2-0 as Brock Purdy’s replacement, leading a come-from-behind drive to win it Sunday for the 3-0 but battered 49ers. The Jaguars are 2-1 thanks to 9 turnovers on defense. They beat Houston at home Sunday but won’t have the Florida heat to help them this week. Hold on tight, CMC.”

NFL power rankings Week 4: Where are San Francisco 49ers, Jacksonville Jaguars ranked now?

The site’s formula predicts that the Jaguars will win the NFL Week 4 game against the 49ers.

NFL Week 4 odds: Point spreads, moneylines, over/unders for Jaguars vs 49ers, other games

ESPN: 49ers have a 49.9% chance to beat Jaguars on Sunday

The site gives the Jaguars a 49.7% shot at winning the NFL Week 4 game, with the remaining percentage accounting for a tie.

NFL Week 4 schedule: Television channels, how to watch, how to stream 49ers vs Jaguars, other games

Dimers: 49ers 26, Jaguars 22

It writes: “After extensive simulations, our model gives the Jaguars a win probability of 33%, while the 49ers have a win probability of 67%.”

Sportsnaut: 49ers 23, Jaguars 17

Matt Johnson writes: “This might be one of the most underrated games on the NFL schedule this weekend. Much of the Jacksonville Jaguars‘ success this season is thanks to a defense that leads the league in takeaways (nine) and the new-look ground game drawn up by Liam Coen that is averaging 5.1 yards per carry and 141.7 rushing yards per game. Last season, that recipe would’ve led to an upset over the San Francisco 49ers. In 2025, against a defense allowing just 3.7 ypc, that will prove harder. If the Jaguars knock out the 3-0 49ers, it will once again be thanks to this defense’s ability to create interceptions.”

NFL’s highest paid players in 2025: Quarterbacks | Running backs | Wide receivers | Tight ends | Offensive linemen | D-linemen | Cornerbacks | Safeties | Linebackers | Edge rushers | Highest paid NFL players: Overall | By position | By team

Reach Jeremy Cluff at jeremy.cluff@arizonarepublic.com. Follow him on X, formerly Twitter @Jeremy_Cluff.

Support local journalism: Subscribe to azcentral.com today.



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