by Rod Pearson
Friday, Sep 19, 2025
Game Time: 4:25 pm ET, Sunday, September 21, 2025
Venue: Levi's Stadium, Santa Clara, CA
Where to Watch: FOX
Opening Odds at USA Sportsbooks
DraftKings: Point Spread: Cardinals +3, 49ers -3; Over/Under: 45.5 points
Bet365: Point Spread: Cardinals +2.5, 49ers -2.5; Over/Under: 45.5 points
BetMGM: Point Spread: Cardinals +2.5, 49ers -2.5; Over/Under: 45.5 points
Season Record
Arizona Cardinals: 2-0 (2nd place, NFC West)
San Francisco 49ers: 2-0 (1st place, NFC West)
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Recent Form
Arizona Cardinals: won their last game at home against the Carolina Panthers 27-22.
San Francisco 49ers: won their last game on the road against the New Orleans Saints 26-21.
Arizona Cardinals vs San Francisco 49ers Preview and Analysis
The Cardinals are entering this game with a 2-0 record overall and they have a 0-0 record in their divisional games too. They are 1-0 in their home games, 1-0 in their road games, and they are also 0-0 in their neutral site games this season, but they will be on the road for this game. They won their last game against the Carolina Panthers 27-22. Kyler Murray was the starting QB and he completed 17/25 passes for 220 passing yards, 1 touchdown, and 1 interception. James Conner led the team in rushing yards with 34 and 1 TD. Trey McBride led the receivers with 78 receiving yards on 6 receptions. Jalen Thompson led the defense in that game with 6 solo tackles and 4 assisted tackles while Calais Campbell led the defense in sacks with 2. Baron Browning came away with the only interception for them in that one.
The 49ers are entering this game with a 2-0 record overall and they have a 1-0 record in their divisional games too. They are 0-0 in their home games, 2-0 in their road games, and they are also 0-0 in their neutral site games this season, but they will be at home for this game. They won their last game against the New Orleans Saints 26-21. Mac Jones was the starting QB and he completed 26/39 passes for 279 passing yards, 3 touchdowns, and 0 interceptions. Christian McCaffrey led the team in rushing yards with 55. Jauan Jennings led the receivers with 89 receiving yards on 5 receptions and 1 TD. Fred Warner led the defense in that game with 7 solo tackles and 4 assisted tackles while Upton Stout, Nick Bosa, and Bryce Huff each led the defense in sacks with 1. No one on the defense came away with an interception for them in that one.
Cardinals vs 49ers Prediction
The current betting odds have the 49ers listed as a 3 point favorite in this game according to Draftkings Sportsbook. The 49ers have looked good in their games this season with their 2-0 record overall. They are off a 26-21 win on the road over the Saints in their last one and that isn't a great win against a bad team, but they managed to win that one with their backup QB and they have been finding ways to get the job done in these games. They picked up a road win over the Seahawks in the division in week 1 too so they have a chance to get ahead of the NFC West here, and they have a lot more talent than the Cardinals on both sides of the ball. Meanwhile, the Cardinals have looked good in their games this season with their 2-0 record overall, but they have also played against 2 of the worst teams in the NFL. They won on the road against the Saints 20-13 in week 1 and now they are off a 27-22 win at home over the Panthers. They were great for most of that game, but they collapsed really late in that one and almost coughed up the game in the end. The offense has a lot of talent, but they will struggle against this 49ers defense which will be the best defense they have seen yet. Their defense also showed some big holes with that late comeback last week and the 49ers still have a lot of talent in that offense, even with all of their injuries. Purdy could be back for the 49ers in this one too, but Mac Jones didn't look bad last week and Shanahan has shown many times that he can win games with a game manager. Even with all of their early injuries, the 49ers are still the better team at home here and have a chance to take an early lead in the division. The best way to place a bet here is on the 49ers to cover the spread in this game.
Cardinals 49ers Prediction: Our NFL Pick for Sunday, September 21, 2025 (4:25 pm ET start time) is 49ers 21 Cardinals 13.
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NFL Betting Trends
Arizona Cardinals: 21-15 ATS in all games. 8-2 ATS as a road underdog of 7 points or less. 4-1 ATS after a win by 6 or less points. 17-10 OVER in games played on a grass field.
San Francisco 49ers: 16-22 ATS in all games. 1-8 ATS in a home game where the total is greater than or equal to 45.5. 5-11 ATS after playing their last game on the road. 7-4 OVER as a home favorite of 7 points or less.
Key Injuries
Arizona Cardinals: W. Johnson (CB) Injured - Groin. M. Melton (CB) Injured - Knee. T. Reiman (TE) Injured - Foot. C. Simon (LB) Injured - Concussion. K. Beachum (OG) Injured - Rest. W. Hernandez (OG) Injured - Knee. P. Johnson Jr. (OG) Injured - Knee. D. Stills (DL) Injured - Elbow.
San Francisco 49ers: J. Watkins (WR) Injured - Calf. N. Bosa (DL) Injured - Rest. B. Purdy (QB) Injured - Shoulder. J. James (RB) Injured - Finger. Y. Gross-Matos (DL) Injured - Knee. K. Juszczyk (FB) Injured - Concussion. S. Burford (OG) Injured - Knee. S. Neal (CB) Injured - Concussion. T. Williams (OT) Injured - Knee. J. Jennings (WR) Injured - Ankle. C. McCaffrey (RB) Injured - Calf.
Notable Quotes
“Ultimately, we made enough plays to win the game. I obviously have to do a much better job making our guys, all three phases, understand how to close games out. I've got a lot of work to do.” - Jonathan Gannon after his team’s win against the Panthers in their last game.
“It’s awesome however you do it. We did have to overcome a number of injuries. We’re real proud of the effort.” - Kyle Shanahan after his team’s win against the Saints in their last game.
Starting Lineups
Arizona Cardinals
WR Harrison Jr., Marvin
WR Jones, Zay
WR Wilson, Michael
TE McBride, Trey
QB Murray, Kyler
RB Conner, James
San Francisco 49ers
WR Bourne, Kendrick
WR Pearsall, Ricky
WR Jennings, Jauan
TE Tonges, Jake
QB Jones, Mac
RB McCaffrey, Christian
FB Juszczyk, Kyle
Statistical Leaders
Arizona Cardinals
Passing: K. Murray (383)
Rushing: T. Benson (83)
Receiving: T. McBride (139)
Touchdowns: J. Conner (2)
San Francisco 49ers
Passing: M. Jones (279)
Rushing: C. McCaffrey (124)
Receiving: R. Pearsall (164)
Touchdowns: G. Kittle (1)
Coaches:
Arizona Cardinals: Jonathan Gannon (3rd season)
San Francisco 49ers: Kyle Shanahan (9th season)
Rod Pearson
About the Author:
Rod Pearson has been a rabid sports fan his entire life. He grew up in Ontario, and was skilled in both hockey and baseball, and pitched in an elite baseball league for many years. In 2022, Rod decided to hang up his glove, so that he could write about the sports he loves -- but from a gambling perspective. Join Rod every day as he breaks down the games to find the best betting value.
