Jaguars vs. 49ers Prediction, Odds, Spread, Injuries, Trends for NFL Week 4

Betting odds, pick and prediction for the Jacksonville Jaguars-San Francisco 49ers matchup in Week 4.

The San Francisco 49ers and head coach Kyle Shanahan are favored in Week 4. / Matthew Hinton-Imagn Images

The San Francisco 49ers are one of six teams that have yet to lose in the2025 season, and they’ll look to keep that going at home in Week 4 against Trevor Lawrence and the Jacksonville Jaguars.

Jacksonville is off to a 2-1 start in Liam Coen’s first season as the team’s head coach, knocking off the Houston Texans in Week 3. Trevor Lawrence and the Jags have not been elite on the offensive end, but they’ve come up with timely plays on both sides of the ball to secure two early wins in 2025.

The big question in this Week 4 matchup is whether or not Brock Purdy will suit up for San Francisco. The star quarterback missed the last two games with turf toe, but 49ers head coach Kyle Shanahan has hinted that the quarterback will return to practice ahead of Week 4.

While the 49ers are 2-0 with Mac Jones under center, there’s no doubt that they’re a better team with Purdy in the lineup. San Fran has been ravaged by injuries in 2025, losing George Kittle, Brandon Aiyuk, Nick Bosa (out for the season), Jauan Jennings and others for games already. 

Still, oddsmakers have the 49ers set as home favorites in this Week 4 battle.

Here’s a breakdown of the odds, players to watch and my prediction for Sunday’s matchup. 

Jaguars vs. 49ers Odds, Spread and Total

Odds via DraftKings Sportsbook

Spread

• Jaguars +3 (-102)
• 49ers -3 (-118)

Moneyline

• Jaguars: +154
• 49ers: -185

Total

• 47.5 (Over -105/Under -115)

Jaguars vs. 49ers How to Watch

• Date: Sunday, Sept. 28
• Time: 4:05 p.m. EST
• Venue: Levi’s Stadium
• How to Watch (TV): FOX
• Jaguars record: 2-1
• 49ers record: 3-0

Jaguars vs. 49ers Betting Trends

• The Jaguars are 2-1 against the spread this season.
• Jacksonville is 0-1 against the spread on the road.
• The 49ers are 2-1 against the spread this season.
• San Francisco is 0-1 against the spread at home. 
• The UNDER is 2-1 in the Jaguars’ games this season.
• The UNDER is 2-1 in the 49ers’ games this season.
• San Francisco is 1-0 ATS and 1-0 to the UNDER when Brock Purdy starts in 2025.

Jaguars vs. 49ers Injury Reports

Jaguars Injury Report

• Wyatt Milum – questionable
• Dyami Brown – questionable

49ers Injury Report

• Nick Bosa – out
• George Kittle – out
• Brandon Aiyuk – out
• Mac Jones – questionable
• Brock Purdy – questionable
• Jauan Jennings – questionable
• Jordan Watkins – questionable
• CJ West – questionable
• Mykel Williams – questionable
• Renardo Green – questionable

Jaguars vs. 49ers Key Player to Watch

Brian Thomas Jr., Wide Receiver, Jacksonville Jaguars

If the Jacksonville offense is going to make a splash in the 2025 season and take this team to the playoffs, then 2024 first-round pick Brian Thomas Jr. has to play better.

BTJ was a sensation in his rookie season, finishing with 87 catches for 1,282 yards and 10 scores, giving Jacksonville a true No. 1 option on the outside. Unfortunately, that has not carried into the 2025 season, as the second-year receiver has just seven catches for 115 yards in three games. 

His lone touchdown came on a nine-yard run, and the Jaguars have struggled to get their passing game going all season, ranking 21st in the NFL in EPA/Pass.

Can Thomas get back on track against a 49ers defense that has allowed the fifth-fewest passing yards in the NFL this season? 

Jaguars vs. 49ers Prediction and Pick

If you’re going to bet on the 49ers in this game, taking them early in the week may be the best move.

The spread has yet to move through the key number of 3 (currently 49ers -3), and there’s a chance that this line moves in San Fran’s favor if Purdy is able to suit up on Sunday.

San Francisco ranks fourth in the NFL in defensive EPA/Play this season, and while it did lose Nick Bosa in Week 3, it still held the Arizona Cardinals to less than 20 points in a win.

Jacksonville, on the other hand, is just in the middle of the pack in EPA/Play on offense despite facing some favorable opponents in the Carolina Panthers and Cincinnati Bengals in Weeks 1 and 2. 

Trevor Lawrence has thrown as many interceptions (four) as he has touchdowns this season, and I am skeptical of this offense that has relied heavily on the run (top-10 in EPA/Rush) against a 49ers team that is allowing just 3.7 yards per carry this season.

If Purdy plays, it’s an all-around boost to this San Francisco attack on the offensive side of the ball. 

I love the 49ers at home in Week 4. 

Pick: 49ers -3 (-118 at DraftKings)

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Odds refresh periodically and are subject to change.

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