49ers vs. Cardinals 2025 Prediction, Odds, Picks - Sep 21

The San Francisco 49ers (2-0) are slim favorites (-1.5) versus the Arizona Cardinals (2-0) in a battle of two division rivals. The matchup has an over/under of 44.5 points.

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49ers vs. Cardinals Odds & Betting Lines

49ers vs. Cardinals Prediction & Pick

• Pick ATS: Cardinals (+1.5)
  
• Pick OU: Over (44.5)
  
• Prediction: Cardinals 25 - 49ers 22

How to Watch San Francisco vs. Arizona

• Game date: Sunday, September 21, 2025
• Time: 4:25 p.m. ET
• Venue: Levi's Stadium
• Location: Santa Clara, California
• TV: Watch on FOX
• Streaming: FOXSports.com, FOX Sports App and FOX One (Try free for 7 days)

49ers vs. Cardinals Recent Matchups

• Over their last five meetings, San Francisco has tallied three wins against Arizona.
• Arizona has been outscored by 36 points in its last five tilts versus San Francisco.

San Francisco Betting Info

• Thus far this season, San Francisco is unbeaten against the spread.
• The 49ers have covered the spread when playing as at least 1.5-point favorites in two of two games this season.
• San Francisco games this year have hit the over on one of two set point totals (50%).
• The 49ers have been moneyline favorites in two other games this season, and they won both.
• Looking at this contest's moneyline, the 49ers' implied win probability is 55.6%.

49ers Stats

San Francisco's Key Players

Offense

• Christian McCaffrey has put up 124 rushing yards without a rushing TD (62.0 yards per game across two games). His 3.5 yards per attempt rank 32nd in the league.
• He has hauled in 15 passes (on 17 targets) for 125 receiving yards with one touchdown. He's averaging 62.5 receving yards and 7.5 catches per game.
• Mac Jones has 279 passing yards, three touchdowns and zero interceptions this year. He has completed 66.7% of his passes, averaging 279.0 yards per game and 7.2 per attempt.
• Brock Purdy has 277 passing yards, two touchdowns and two interceptions this year. He has completed 74.3% of his passes, averaging 277.0 yards per game and 7.9 per attempt.
• He has tacked on 17 rushing yards (17.0 per game) without a touchdown on the ground.
• Jauan Jennings has racked up 105 receiving yards and one touchdown with seven catches on 15 targets. He is averaging 3.5 receptions and 52.5 yards per game.

Defense

• On the defensive side for the 49ers, Nick Bosa has racked up 15 tackles, 4.0 TFL, and two sacks in 2025.
• Fred Warner has 19 tackles and 2.0 TFL this season. His tackle total leads the 49ers.
• This season, Dee Winters has put up 2.0 TFL and 14 tackles.
• Marques Sigle has 11 tackles on the season.

Arizona Betting Info

• Arizona has covered the spread one time this year (1-1-0).
• Arizona games have gone over the total once this season.
• The Cardinals have not played a game this season while listed as the underdog.
• The oddsmakers' moneyline implies a 48.8% chance of a victory for the Cardinals.

Cardinals Stats

Arizona's Key Players

Offense

• In two games played this year, Kyler Murray has totaled 383 passing yards, while throwing three touchdowns against one interception and completing 70.4% of his passes.
• Murray has also rushed for 70 yards (third on the Cardinals).
• James Conner has 73 rushing yards (second on the Cardinals) and one rushing touchdown, while averaging 36.5 yards per game and 3.2 per carry (38th in the NFL).
• Conner has added five receptions (2.5 per game) for 23 yards (11.5 per game) with one receiving touchdown. He's been targeted five times in the passing game.
• Through two games played this season, Marvin Harrison Jr. has seven catches (3.5 receptions per game on 5.5 targets per game) for 98 yards and one receiving touchdown.
• Trey McBride has 12 catches for 139 yards without a receiving touchdown. He averages 6.0 yards per game in two games and has been targeted 16 times.

Defense

• Calais Campbell's 2025 showing includes 10 tackles, 2.0 TFL, and two sacks through two games. He is fifth on the Cardinals in tackles.
• Mack Wilson has 1.0 TFL and 16 tackles.
• Budda Baker has recorded 1.0 TFL and 18 tackles in the 2025 season.
• Baron Browning has registered 1.0 sack (second on the Cardinals) to go with 2.0 TFL, six tackles, and one interception over two games.

FOX Sports created this story using technology provided by Data Skrive and data from Sportradar.

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San Francisco 49ers

Arizona Cardinals