Two of the three unbeaten teams from the NFC West meet Sunday afternoon in Northern California as the Arizona Cardinals (2-0) square off against the San Francisco 49ers (2-0).
This is the 49ers home opener following wins at Seattle (17-13) and at New Orleans (26-21). With Brock Purdy (left shoulder/toe) sidelined, Mac Jones led San Francisco to the win throwing for 279 yards passing including three touchdown passes without an interception.
The Cardinals earned their second win last week nearly blowing a 27-3 lead before ultimately holding on for a 27-22 victory. Arizona failed as a team to gain 300 yards in the game (292) and committed 12 penalties for 96 yards but found a way to win and set up this weekend’s matchup of unbeatens.
Lets take a deeper dive into this Week 3 NFC West showdown between the Cardinals and the 49ers.
NBC Sports has all the latest info and analysis you need, including how to tune in for kickoff, odds from DraftKings, player news and updates, and of course our predictions and best bets for the game from our staff of experts.
Game Details and How to watch the Arizona Cardinals at the San Francisco 49ers live Sunday
- Date: Sunday, September 21, 2025
- Time: 4:25PM EST
- Site: Levi’s Stadium
- City: Santa Clara, CA
- Network/Streaming: FOX
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Game odds for Arizona at San Francisco
The latest odds as of Sunday courtesy of DraftKings:
- Moneyline: Arizona Cardinals (+136), San Francisco 49ers (-162)
- Spread: 49ers -2.5
- Total: 45.5 points
This game opened at 49ers -1.5 with the Game Total set at 42.50.
Be sure to check out DraftKings for all the latest game odds & player props for every matchup this week on the NFL schedule!
Quarterback Matchup for Arizona at San Francisco
- Cardinals Expected Starting QB: Kyler Murray
Last Game: 9/14 vs. Carolina - 17-25 (68%), 220yds, 1 TD, 1 INT, Sacked 1 time, 7 carries for 32yds
Season: 2GP, 38-54 (70.4%), 383yds, 3 TDs, 1 INT, Sacked 6 times, 14 carries for 70yds - 49ers Expected Starting QB: Mac Jones
Last Game: 9/14 at New Orleans - 26-39 (66.7%), 279yds, 3 TDs, 0 INT, Sacked 3 times, 6 carries for 6yds
Season: 2GP, 26-39 (66.7%), 279yds, 3 TDs, 0 INT, Sacked 3 times, 6 carries for 6yds
Cardinals at 49ers team stats, betting trends
- The 49ers have won 12 of their last 20 home games
- The Cardinals went 11-6 against the spread last season
- 5 of the 49ers’ last 7 games (71%) have gone over the Total
Cardinals Player Injuries
- LT Paris Johnson Jr. (undisclosed) is listed as questionable for Sunday’s game
- CB Will Johnson (groin) is listed as questionable for Sunday’s game
- CB Max Melton (knee) is listed as questionable for Sunday’s game
- TE Tip Reiman (foot) is listed as questionable for Sunday’s game
- RG Will Hernandez (undisclosed) is listed as questionable for Sunday’s game
- DT Walter Nolen III (undisclosed) has been declared out of Sunday’s game
- DT Dante Stills (undisclosed) is listed as questionable for Sunday’s game
- LB Cody Simon (undisclosed) is listed as questionable for Sunday’s game
- CB Garrett Williams (knee) was placed on IR Wednesday and has been declared out of Sunday’s game
- DE L.J. Collier (knee) was placed on IR Wednesday and has been declared out of Sunday’s game
49ers Player Injuries
- QB Brock Purdy (shoulder/toe) is listed as questionable for Sunday’s game
- Jauan Jennings (ankle/shoulder) is listed as questionable for Sunday’s game
- FB Kyle Juszczyk (concussion) is listed as questionable for Sunday’s game
- LT Spencer Burford (knee) is listed as questionable for Sunday’s game
- DE Yetur Gross-Matos (undisclosed) is listed as questionable for Sunday’s game
- CB Siran Neal (concussion) is listed as questionable for Sunday’s game
- LG Ben Bartch (ankle) was placed on IR Wednesday and has been declared out of Sunday’s game
Rotoworld Bet Best Bets
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Drew Dinsick (@whale_capper): Game Total OVER 44 (-108)
A cluster injury for the Cardinals secondary comes at an inopportune time as they face a dynamic passing scheme on the road. They can answer however as the scrambling of Murray and intermediate attack with Trey McBride will open the door for a back and forth scoring environment.
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Our model calculates projections around each moneyline, spread and over/under bet for every game on the NFL calendar based on data points like past performance, player matchups, stadium information and weather forecasts.
Once the model is finished running, we put its projection next to the latest betting lines for the game to arrive at a relative confidence level for each wager.
Best bets our model is projecting for this week’s game between the Cardinals and the 49ers:
- Moneyline: NBC Sports Bet is staying away from a play on the Moneyline.
- Spread: NBC Sports Bet is leaning towards a play ATS on the San Francisco 49ers at -1.5.
- Total: NBC Sports Bet is recommending a play on the under on the Game Total of 45.5.
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Follow our experts on socials to keep up with all the latest content from the staff:
● Jay Croucher (@croucherJD)
● Drew Dinsick (@whale_capper)
● Vaughn Dalzell (@VmoneySports)
● Trysta Krick (@Trista_Krick)
