The San Francisco 49ers' injury woes this season have primarily hit the offense, and Week 3's NFC West bout against the Arizona Cardinals was already impacted with tight end George Kittle still on injured reserve, quarterback Brock Purdy still sidelined with a toe issue and wide receiver Jauan Jennings out with shoulder and ankle injuries.
Those absences were felt early, as Arizona's offense dominated the time of possession during the first quarter, leaving coordinator Robert Saleh's defense under siege for the bulk of the first half.
If that wasn't bad enough, watching All-Pro defensive end Nick Bosa leave the game late in the first quarter with what was reported as a knee injury only makes things worse.
Bosa went down awkwardly with two Arizona offensive linemen landing on top of him, and the pass-rusher gingerly walked off the field and into the blue medical tent. The Fox Sports broadcast showed him wincing but able to walk around while being tended to by the Niners' medical staff.
Nick Bosa is headed to the locker room after an apparent injury. pic.twitter.com/f877GmVWtD
— FOX Sports: NFL (@NFLonFOX) September 21, 2025
Unfortunately, that quick attention wasn't able to keep Bosa from departing back to the locker room early in the second quarter.
49ers will have trouble making up for Nick Bosa's absence
San Francisco's offense, led by No. 2 quarterback Mac Jones, struggled to find any rhythm during the first quarter-plus, going 3-and-out on its first two drives and hardly biting into the clock.
With just under nine minutes left in the second quarter, the 49ers possessed the ball for a mere two minutes and 19 seconds, whereas the Cardinals had the ball for nearly 19 minutes, putting extensive pressure on Saleh and Co. to hold the line.
And they may now need to do so without Bosa, whose return remains very much up in the air.
In the interim, the Niners turned to fellow pass-rushers like Bryce Huff and rookie Mykel Williams to shoulder the load from the edge, but even that took a hit with Williams being ruled questionable to return, too, with an undisclosed injury.
But, until San Francisco's offense gets into a rhythm, the defense might continue to be under siege for the bulk of the first half, if not the rest of the game.
Editor's update: At the start of the third quarter, the NFL feed reported Bosa's status as OUT for the rest of Week 3.