The San Francisco 49ers have been bitten hard by the injury bug so far this season, but the latest loss in the Bay may be too much to overcome. Star pass rusher Nick Bosa is out for the rest of the year after suffering yet another ACL tear.

The 49ers’ opponent this week, the Jacksonville Jaguars, are 2-1, but they have yet to beat a contending opponent, and Trevor Lawrence has not looked sharp. Last week’s win over the Houston Texans saw him complete just 50 percent of his passes and throw for a mere 222 yards on 40 attempts with an interception and no TDs. With so many familiar faces gone and now Nick Bosa injured, if Lawrence is going to live up to his draft and contract status, it will need to happen against an undefeated 49ers team.

Here is who our staff is picking to win between the 49ers and Jaguars.

Jaguars 25, 49ers 20

I believe in Liam Coen as a playcaller. The jury is still out on him as a head coach, but he’s going to be like a shark that smells blood with Bosa now out. He will craft a game plan that asks Lawrence to play to his strength’s and I believe that will be enough to get past a depleted 49ers unit.

Offensively, there are still questions about who will start at QB for San Francisco as of publication, and I think a Jaguars defense that held their opponents to a combined 20 points in Weeks 1 and 3 (albeit against incompetent offenses) will do enough to slow down the 49ers.

– Rob Gregson, A to Z Sports Pittsburgh

Jaguars 27, 49ers 17

“Two teams who have flirted with losses a couple times this year but have been able to squeak out wins, with the undefeated 49ers taking on the 2-1 Jaguars. Just like a year ago the 49ers have been hit hard with injuries already to start the 2025 season but they’ve been able to over come them through the first three weeks.”

“I think their luck runs out this week, following Nick Bosa tearing his ACL. I think their stout defense is going to suffer some massive regression, and the new look Jaguars offense will take advantage. I’m going to take the Jaguars to win by two scores and I think this will be a get-right game for Brian Thomas whose sophomore year isn’t starting out as strong as his fantastic rookie year.”

– Destin Adams, A to Z Sports Indianapolis

49ers 21, Jaguars 17

“The 49ers just feel inevitable so far this season. Shorthanded, injury-riddled, and inexperienced – those pieces of the puzzle haven’t stopped them from a 3-0 start to the campaign. Losing Nick Bosa for the season may be the biggest loss of the season for them so far, though, and that will be felt throughout their defense going forward. Young players will have to step up. This game will be closer than some may believe since the Jags haven’t been overly impressive on either side of the football.”

“Give me San Fran in a matchup that may force some fans to shield their eyes from at some points. It’s a sloppy 49ers home win to get to 4-0, somehow.”

– Adam Holt, A to Z Sports New Orleans

49ers 17, Jaguars 14

“As long as Kyle Shanahan is the 49ers’ head coach, the team will always have a shot. But it’s getting harder and harder to overcome so many injuries. This week, the defense lost star edge rusher Nick Bosa for the season with a torn ACL, and he joins players like Brandon Aiyuk and George Kittle on injured reserve. However, quarterback Brock Purdy has a chance to return.”

“It’s hard to evaluate the chances of each team in a game like this before knowing for sure which quarterback will play, but the 49ers’ offense has operated at a decent level even with Mac Jones over the past few weeks. If Purdy plays, the Niners’ chances obviously increase significantly. But the return of defensive coordinator Robert Saleh has been massive for the unit, and the floor week in and week out is clearly much higher. Even though the Jaguars have shown good signs early in the season, I’m still going with the 49ers for this one.”

– Wendell Ferreira, A to Z Sports Green Bay

49ers 20, Jaguars 13

“Mac Jones, you sly dog! Jones and the 49ers lulled Arizona to sleep in Week 3 before breaking out the situational football in a big way to steal a one-point win over the Cardinals. Meanwhile, the Jaguars are living their best life under defensive coordinator Anthony Campanile.”

“They’ve posted nine turnovers in three games. Whether it’s Jones or Brock Purdy in Week 4, their hands will be full with Jacksonville’s aggressive defense. But I trust San Francisco at home with either quarterback to make enough plays as compared to what I think Jacksonville gets going on offense against the 49ers.”

– Kyle Crabbs, A to Z Sports NFL

Jaguars 24, 49ers 17

“49ers coach Kyle Shanahan deserves a lot of credit for maneuvering his team through all their injury woes en route to a 3-0 start. However, I can’t help but think it’s going to catch up with them sooner than later. Losing defensive end Nick Bosa is a major blow for San Francisco’s defense, which has been stellar so far.”

“Liam Coen is changing the culture in Jacksonville and has his young team buying in. The Jaguars have enough talent on offense to have a solid day against the banged up 49ers’ defense. Speaking of defenses, the Jags have quietly played well on that side of the ball this season, allowing just 17 points per game and ranking fifth against the run.”

– Nick Roesch, A to Z Sports Kansas City

Final Prediction for 49ers vs. Jaguars

Our crew was split on the result of this one, which hopefully signals a competitive game in the late afternoon slate. One team is hungry and out to prove, while the other is aiming to both remain perfect and stay afloat.

Sunday should be fun.

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