San Francisco 49ers vs Arizona Cardinals Picks and Prediction for Sunday, November 16, 2025
Use Code WWWC We have a key NFC West matchup in this 49ers vs. Cardinals prediction. On Sunday, the San Francisco 49ers (6-4, 3rd NFC West) visit the Desert Southwest for an NFC West showdown with the Arizona Cardinals (3-6, 5th NFC West). San Francisco lost to the Los Angeles Rams 42-26 last weekend for their second loss in the last three games. San Francisco is 3rd in the NFC West, 1.5 games behind co-leaders Seattle and Los Angeles. Arizona lost to the Seattle Seahawks 44-22 last weekend and has lost six of the last seven. The Cardinals are last in the NFC West. Make sure to read this in-depth San Francisco 49ers vs Arizona Cardinals prediction. Stay sharp this week with expert NFL picks for the San Francisco 49ers at the Arizona Cardinals prediction and crush the lines.
San Francisco needs to improve on both sides of the ball
The San Francisco 49ers are 23rd in scoring at 22.0 points per game and 11th in total offense at 356.2 yards per game. San Francisco's running game is 27th, and its passing attack is 1st. The San Francisco defense allows an average of 23.0 points per game, which is 15th, and the 49ers allow an average of 339.4 yards per game, which is 21st. San Francisco's defense is 16th in rushing yards allowed and 22nd in passing yards allowed.
San Francisco quarterback Brock Purdy, who has thrown for 586 yards with four touchdowns and four interceptions, is practicing and is expected to start on Sunday. Mac Jones, who has thrown for 2,151 yards with 13 touchdowns and six interceptions, has done a solid job in his place. Christian McCaffrey leads the 49ers in both rushing and receiving, with 626 yards on the ground and 692 yards receiving. McCaffrey has a combined 8 TDs. LB Dee Winters is the leading tackler with 67. The 49ers’ defense has made 12 quarterback sacks and intercepted one pass.
Key Injury Report for 49ers
- LB Dee Winters (knee) is questionable
- CB Deommodore Lenoir (calf) is questionable.
Arizona needs to find a way to score more points
The Arizona Cardinals will play without starting QB Kyler Murray as well as No. 1 WR Marvin Harrison Jr. The Cardinals are 20th in scoring, averaging 22.4 points per game, and 21st in total offense, averaging 316.3 yards per game. Arizona is 19th in rushing yards per game and 21st in passing yards per game. The Arizona defense allows 23.9 points per game, which is 19th, and 339.4 yards per game, which is 22nd. The Cardinals are 18th in rushing yards allowed and 20th in passing yards allowed per game,
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With Kyler Murray on injured reserve, Jacoby Brissett will start under center for Arizona. Brissett has 1,118 yards passing with eight touchdowns and one interception, but has been sacked 18 times in six games. Emari Demercado is the leading rusher for Arizona with 233 yards, while the leading receiver is TE Trey McBride with 603 yards and six touchdown receptions. Linebacker Akeem Davis-Gaither is the leading tackler for Arizona with 64. The Cardinals’ defense has made 18 quarterback sacks and intercepted six passes
Key Injury Report for Cardinals
- WR Marvin Harrison Jr. (appendicitis) is out
- QB Kyler Murray (foot) is on the IR.
- OT Kelvin Beacham is questionable.
- CB Max Melton (concussion) is questionable.
San Francisco 49ers vs. Arizona Cardinals Pick
Spread Pick for San Francisco 49ers vs. Arizona Cardinals
- San Francisco 49ers -2.5 ( units)
The San Francisco 49ers may have starting quarterback Brock Purdy back under center, but backup Mac Jones has performed well in Purdy’s absence since week 5. The 49ers have the best passing attack in the NFL, averaging 261.4 yards per game, but could be without their leading rusher and receiver, Christian McCaffrey, who is questionable. Arizona will have backup quarterback Jacoby Brissett under center, and the Cardinals are without No. 1 receiver Marvin Harrison Jr. San Francisco will attack an Arizona pass defense that is 20th in the NFL, allowing an average of 225.3 yards per game. San Francisco defeated Arizona 16-15 at home in the first meeting earlier this season in Week 3, but the Cardinals had starting QB Kyler Murray and Marvin Harrison Jr, while this time, both are out.
Look over each team's injury report before Sunday's kickoff.
Over/Under Pick for San Francisco 49ers vs. Arizona Cardinals
- Under 48.5 ( units)
Although the total has finished over in six of San Francisco's 10 games this season, one of the games that finished under with just 31 points scored was against Arizona in Week 3. Arizona will be without starting quarterback Kyler Murray and wide receiver Marvin Harrison Jr. They're going up against a solid defense without some explosive weapons. Look for a game that will be dominated by the defense on both sides of the line of scrimmage, with points coming at a premium and much of the game played between the 20-yard lines.
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