The San Francisco 49ers (6‑4) and the Arizona Cardinals (3‑6) will meet in an important NFC West matchup on Sunday afternoon. The 49ers enter this game trying to catch up to the Seahawks and Rams in the NFC West, while the Cardinals try to figure things out amid a quarterback change. Before kickoff from Glendale, you can find my 49ers vs Cardinals prediction right here.
Our 49ers vs Cardinals Pick
- Pick: San Francisco 49ers −3
- Confidence: ★★★☆☆
Game Snapshot
- Matchup: San Francisco 49ers vs Arizona Cardinals
- Date & Time: Sunday, November 16, 2025, 4:05 PM ET
- Venue: State Farm Stadium, Glendale, Arizona
- Broadcast: FOX
Key Storylines
- The 49ers are expected to get their starting quarterback Brock Purdy back after a six‑game absence due to turf‑toe injury. He has ramped up practice reps and is trending toward returning this week.
- The Cardinals will be without rookie wide receiver Marvin Harrison Jr., who underwent appendicitis surgery and is ruled out for this game. He has 34 catches for 525 yards and 4 touchdowns this season.
- The 49ers’ defense has been inconsistent. They gave up 42 points in their most recent game against the Rams and rank poorly in success‑rate allowed.
- The Cardinals are in the midst of a quarterback change. Jacoby Brissett is taking over for the injured Kyler Murray again here.
Quarterback Play
Purdy’s return is significant for San Francisco. The 49ers were 6‑4 without him and have shown resilience, but Purdy’s mobility and chemistry with key targets should help the Niners in a big way. Arizona backup Jacoby Brissett is starting in place of the injured Kyler Murray. Brissett hasn’t been bad in Murray’s place this season. He has eight touchdown passes and just one interception so far this year. While Brissett has been steady, Harrison’s absence and a difficult opponent make this a tougher challenge for him in Week 11.
Betting Trends & H2H
- The 49ers are 5-5 against the spread this season.
- Arizona is 5-4 against the spread entering Week 11 competition.
- The Cardinals have gone over the total in five of their first nine games.
- San Francisco is 6-3-1 to the over going into this game.
- San Francisco beat the Cardinals in their first matchup of this season by one point.
49ers vs Cardinals Model Projection
Score Projection: San Francisco 49ers 27 – Arizona Cardinals 17
Win Probability: San Francisco 49ers 58 %, Arizona Cardinals 42 %
Final Thoughts
I’ll lay the field goal with the 49ers in this NFC West matchup. The Niners have to get this game to avoid falling further behind the winner of Sunday’s game between the Seahawks and Rams. I think they will get the win with their starting quarterback under center once again.
