Arizona Cardinals vs San Francisco 49ers Pick – 9/21/2025
The Arizona Cardinals and San Francisco 49ers will meet in Week 3 of the NFL season. These two NFC West rivals are both 2-0 to start the season. The Niners are slight favorites as they look to keep their zero in the loss column. Here, I break down this game between division rivals and make my Cardinals vs 49ers prediction in a game that will decide who has the early lead in the NFC West standings.
Our Cardinals vs 49ers Pick
- Pick: 49ers -1.5
- Confidence: 3/5
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Game Snapshot
- Matchup: Arizona Cardinals vs San Francisco 49ers
- Date & Time: Sunday, September 21, 4:25 p.m. ET
- Venue: Levi’s Stadium, Santa Clara, CA
- Broadcast: FOX
Key Storylines
- The Niners are expected to be without Brock Purdy again in this game. Mac Jones looked solid in his place in Week 2. But there is no guarantee that will remain the case in this contest against an unbeaten opponent.
- The Cardinals are 2-0 and have taken advantage of a very weak early-season schedule. They have beaten the New Orleans Saints and Carolina Panthers so far. This will be a tougher test for Arizona, even with Mac Jones likely at quarterback.
- Trey McBride is off to a great start at tight end for the Cardinals. He has 12 catches and 139 receiving yards going into Week 3 and Kyler Murray will continue to look for him in the Arizona passing game.
Quarterback Play
Kyler Murray enters this game having performed efficiently through two weeks. The Cardinals’ signal caller has completed 70% of his passes and has three touchdown passes with just one interception. If Murray can continue to keep the ball out of harm’s way, Murray and the Cardinals could be in for a big year.
Mac Jones takes over for the 49ers with an established supporting cast. Jones had 279 yards, three touchdowns, and no interceptions in Brock Purdy’s place in the team’s Week 2 win over the Saints. George Kittle is unavailable at tight end for the Niners but that didn’t stop Jones from playing well in his first action of the season.
Betting Trends & H2H
- San Francisco is 2-0 against the spread to begin the season.
- Arizona is 1-1 ATS early in the year.
- Both teams are 1-1 in the over/under market going into this contest.
Cardinals vs 49ers Model Projection
Score Projection: Cardinals 20 – 49ers 24
Win Probability: Cardinals 47%, 49ers 53%
Final Thoughts
I don’t think that Mac Jones will be quite as good this week as he was last week. But he is a serviceable backup quarterback who isn’t demonstrably worse than Brock Purdy. He should keep the 49ers offense moving in the right direction in this game, while the Cardinals should experience some regression as they aren’t facing one of the worst teams in the league again. I’ll lay the points with the 49ers here, as their defense should give their offense enough margin for error to get the job done.
