The Arizona Cardinals again found themselves needing a late-game stop to secure a win after holding a lead. They were successful in the first two weeks - though the San Francisco 49ers had other plans.
Arizona fell to 2-1 on the 2025 season after their 16-15 loss to the 49ers in Week 3, which was decided by a game-winning field goal as time expired.
Here's how the action unfolded in Santa Clara:
The 49ers won the coin toss and deferred to the second half - giving Kyler Murray and co. first opportunity to touch the ball.
Despite picking up a few first downs, the Cardinals walked away empty-handed after Chad Ryland missed a 57-yard attempt wide right, which would have been a career high.
Fortunately, for Arizona, Mac Jones (starting in place for Brock Purdy) and the Niners' offense went three-and-out on their first opportunity.
The Cardinals, again, were unable to generate anything on their second drive, though 49ers star Nick Bosa hobbled off the field and went out with a knee injury. He did not return.
A Josh Sweat sack on Jones ended the first quarter with a 0-0 score and San Francisco set to punt once more.
The Cardinals finally found the scoreboard on their third possession, as Ryland booted home a 34-yard try to put Arizona up 3-0.
The 49ers found their footing on their third drive thanks to the arm of Mac Jones, eventually putting Eddy Pineiro in position to put home a 28-yard try to even things up at 3-3.
Pineiro was again called upon to push San Francisco ahead with just 17 seconds left in the first half, this time from 51 yards out.
Huff on the prowl
— San Francisco 49ers (@49ers) September 21, 2025
: FOX
NFL+ // https://t.co/KTh0i4oaLh pic.twitter.com/lMCwQYyiXL
The Cardinals were looking to potentially put themselves in position to score again, though Murray was sacked by Bryce Huff to end the half.
The 49ers were shut down on their first drive of the second half, though things for the Cardinals' offense went from bad to worse when James Conner left with a gruesome ankle injury - which you can read more about here.
The Cardinals had a great shot to take the lead - though Emari Demercado dropped an open pass on third down near the goal line, sending Ryland out for a second successful field goal to knot things up at 6-6 midway through the third quarter.
The 49ers dinked-and-dunked their way down the field - but Arizona's defense stood strong with fourth-and-goal at the one-yard line, as Mack Wilson forced an incomplete pass intended for Christian McCaffrey with just 15 seconds left in the quarter.
that was nasty
— Arizona Cardinals (@AZCardinals) September 21, 2025
FOX | @MackWilSr pic.twitter.com/xUseb3ioWB
The first play in the final quarter brought some controversy, as the 49ers believed they got a safety on Murray, who threw the ball away for intentional grounding near the goal line - though replay showed he wasn't completely in the end zone, and thus the punt team was brought on.
The 49ers, taking over possession around midfield, faced a fourth-and-short but found Ricky Pearsall deep down the right sideline to set San Francisco up for first-and-goal.
4TH AND PEARSALL!
— NFL (@NFL) September 21, 2025
AZvsSF on FOX/FOX Onehttps://t.co/HkKw7uXVnt pic.twitter.com/dAhqo6Khgc
Just a few plays later, Kyle Juszczyk was found by a limping Jones for the game's first touchdown, taking a 13-6 lead with 10:50 left.
Mac Jones to Kyle Juszczyk for the lead!
— NFL (@NFL) September 21, 2025
AZvsSF on FOX/FOX Onehttps://t.co/HkKw7uXVnt pic.twitter.com/gsjSXj1KrK
The Cardinals responded immediately with a 32-yard connection downfield to Marvin Harrison Jr. - and a pass interference on Renardo Green set Arizona up with a first-and-goal at the one-yard line.
Two plays later, Trey McBride was found by Murray for six - and Ryland's extra point again tied the score up, this time at 13-13 with 8:37 remaining.
TD views brought to you by McBride
— Arizona Cardinals (@AZCardinals) September 21, 2025
FOX | @mcbtrey pic.twitter.com/CmN11lvG0o
Looking like the 49ers were about to drive and score to go ahead, Cardinals safety Dadrion Taylor-Demerson stepped in front of a Jones pass and intercepted it, giving Arizona new life.
absolutely ELECTRIC int from Rab ‼️ pic.twitter.com/BFMyXWHako
— Arizona Cardinals (@AZCardinals) September 21, 2025
However, Fred Warner batted down a third-down pass, and the 49ers took over deep in their own territory with things still tied and 3:29 left on the clock.
The Cardinals' defense forced a safety two plays later after Calais Campbell was held in the end zone, pushing Arizona into the lead with a 15-13 advantage.
CALAIS FORCES THE SAFETY
— Arizona Cardinals (@AZCardinals) September 21, 2025
FOX | @CalaisCampbell pic.twitter.com/CS2XhpGxcA
Looking to end the game at the two-minute drill, Arizona thought Zay Jones came down with a crucial catch before the ground jarred possession loose, forcing a punt back to San Francisco with 1:45 left and one timeout.
Jones drove the 49ers' offense down the field with ease, dialing up a screen pass to Christian McCaffrey, who scampered his way into field goal position with just seconds remaining.
Pineiro's 35-yard try was good at the buzzer, handing Arizona their first loss of the season.
Victory vibes in San Francisco pic.twitter.com/LT1k0NXBvz
— NFL (@NFL) September 21, 2025
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