Jacksonville Jaguars vs. San Francisco 49ers: Key Matchups for Sunday

The Jacksonville Jaguars have one of the toughest tests in the early portion of the regular season when they take on the undefeated San Francisco 49ers in Santa Clara for a late Sunday afternoon bout. Jacksonville is one of the most intriguing teams in the NFL, with its rapid resurgence on defense, thanks to the talent they bestow and defensive coordinator Anthony Campanile.

Head coach Liam Coen is looking for momentum and a statement game ahead of the Jaguars' biggest matchup of the year against the Kansas City Chiefs on Monday Night Football in less than two weeks. Let's look at the key matchups that could determine this weekend's dual in wine country.

Christian McCaffrey vs. Jacksonville Jaguars front seven

CMC Jag — Sep 7, 2025; Seattle, Washington, USA; San Francisco 49ers running back Christian McCaffrey (23) runs the ball during the first half against the Seattle Seahawks at Lumen Field. Mandatory Credit: Steven Bisig-Imagn Images | Steven Bisig-Imagn Images

As someone who watched him closely in Carolina in his early years, McCaffrey is one of the best pure offensive playmakers in the league, and at his best, the best running back in football. He is an elite running back and slot receiver all in one: the ultimate playmaker.

This is undoubtedly the best running back the Jaguars have and will face this season. Run fit and key discipline will be a priority for the second level of this unit, Foye Oluokun and Devin Lloyd, and gap and lane integrity from Josh Hines-Allen and Travon Walker. This will be a great test, one that, if Jacksonville succeeds, could shut down the 49ers' offense in a key aspect of their game plan.

Jacksonville Jaguars offensive line vs. San Francisco 49ers defensive line

Harrison Jag — Sep 7, 2025; Jacksonville, Florida, USA; Jacksonville Jaguars offensive tackle Anton Harrison (77) takes the field prior to a game against the Carolina Panthers at EverBank Stadium. Mandatory Credit: Nathan Ray Seebeck-Imagn Images | Nathan Ray Seebeck-Imagn Images

49ers star pass rusher Nick Bosa will miss the remainder of the season with a torn ACL, the same one he injured a few years ago. Now it will be time for first-round selection Mykel Williams to step up and make progress early in his rookie year. Bryce Huff and Yetur Gross-Matos are quality players that can have an affect to an opposing passing game.

Right tackle Anton Harrison and center Robert Hainsey have been the top offensive linemen for the Jaguars through the first three weeks, as their units' work has resulted in the second-fewest pressures allowed this season. Harrison is the star of the show with the second-lowest pressure rate allowed this season, which could help Trevor Lawrence and the offense find a rhythm that has been lacking to start the year.

Jacksonville Jaguars cornerback Tyson Campbell vs. San Francisco 49ers wide receiver Ricky Pearsall

Jacksonville Jaguars cornerback Tyson Campbell (3) breaks a pass intended for Houston Texans wide receiver Nico Collins (12) during the fourth quarter between the Houston Texans and the Jacksonville Jaguars Sunday September 21, 2025 at EverBank Stadium in Jacksonville, Fla. The Jaguars defeated the Texans 17-10. [Doug Engle/Florida Times-Union] | Doug Engle/Florida Times-Union / USA TODAY NETWORK via Imagn Images

Selfishly, this should be Brandon Ayiuk against Campbell, but the All-Pro wideout is still recovering from a torn ACL late last season. Pearsall has been great in his absence, according to NFL Pro, leading the league in yards on downfield targets with 264. It goes to show how good Pearsall is winning quickly at the line of scrimmage and down the field on vertical planes.

This is one of the areas the Jaguars have struggled with defensively, as Campbell, for as good as he has been, has allowed the 6th-most receiving yards of any player on downfield throws this season at 138. If Campbell can win downfield against Pearsall, track, and attack through the receiver or at the catch point, it closes off a key element of the 49ers offense, regardless of who is starting at quarterback.

Coen Jag — Jaguars Head Coach Liam Coen coaches along the sideline during the first quarter between the Houston Texans and the Jacksonville Jaguars Sunday September 21, 2025 at EverBank Stadium in Jacksonville, Fla. [Doug Engle/Florida Times-Union] | Doug Engle/Florida Times-Union / USA TODAY NETWORK via Imagn Images

Follow along on X (Twitter) @JaguarsOnSI and @_John_Shipley and never miss the latest news and analysis on Sunday's game in Santa Clara

Please let us know your thoughts on who you think are the key matchups for this weekend when you like our Facebook page, WHEN YOU CLICK RIGHT HERE.