Arizona Cardinals vs. San Francisco 49ers Picks and Prediction, Sunday, September 21, 2025
An NFC West matchup goes down on Sunday, September 20, as the Arizona Cardinals take on the San Francisco 49ers at 4:25 p.m. ET, so continue reading for our Cardinals vs 49ers prediction. Arizona (2-0) is coming off a 27-22 home win over the Carolina Panthers, while San Francisco (2-0) is coming off a 26-21 win over the New Orleans Saints.
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Cardinals Beat Panthers
Arizona is 2-0 this season and coming off a thrilling 27-22 win over the Panthers at home last week. In the win, the Cardinals were led by Kyler Murray, who went 17-for-25 for 220 yards, one touchdown, and one interception. He also rushed for 32 yards. Running back James Conner, meanwhile, was held to 34 yards rushing, and tight end Trey McBride led the way with six receptions for 78 yards.
The Cardinals are averaging 23.5 points per game through two weeks, as Arizona is averaging 191.5 passing yards and 114 rushing yards per game. Defensively, the Cardinals are allowing 17.5 points per game, as Arizona is allowing 271 passing yards per game and 78 rushing yards per game.
In terms of injuries, Arizona has issues in their defensive backfield. Garrett Williams (knee) was placed on the injured reserve. Max Milton (knee) and Will Johnson (groin) are considered questionable for this game.
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Mac Jones leads 49ers to win over Saints
San Francisco is off to a 2-0 start as the 49ers held on to beat the New Orleans Saints 26-21 on Sunday. The 49ers are expected to start Mac Jones, as Brock Purdy is still injured. However, Purdy (toe) was a limited participant on Wednesday and is considered a "long shot" to play. Jones had a strong game last week, as he went 26-for-39 for 279 yards and threw for three touchdowns against the Saints. RB Christian McCaffrey was a focal point of the offense as he rushed for 55 yards on 13 carries, while adding 52 receiving yards and a touchdown. Jauan Jennings had five receptions for 89 yards and a touchdown.
The 49ers defensively are allowing 17 points per game as opposing teams are averaging just 178.5 passing yards per game and 102.5 rushing yards per game. Offensively, San Francisco is averaging 21.5 points per game, 278 passing yards per game, and 98 rushing yards per game.
TE George Kittle (hamstring) will miss his second straight game. FB Kyle Juszcyzk (concussion) is also not likely to play while Jennings (ankle/shoulder) is questionable.
Cardinals vs. 49ers Pick
Spread Pick for Cardinals vs. 49ers
- 49ers ML -135 (4 units)
Although Purdy and George Kittle are injured, this is still a good spot for the 49ers to get the win at home. Mac Jones played well in his first start, as Kyle Shanahan was able to come up with a good game plan, and that should continue against the Cardinals. Arizona's defense has had some issues this season, as Bryce Young was able to have a ton of success. Meanwhile, the 49ers' defense will be the difference in this one, as San Francisco will be able to get after Murray and limit the passing game to get the win.
Take the 49ers ML.
Over/Under Pick for Cardinals vs. 49ers
- Under 44.5 -115 (4 units)
The under is a great spot here as both the Cardinals and 49ers defense have been solid to begin the season. Meanwhile, both teams like to run the ball, which will help burn the clock out. The 49ers are allowing just 17 points per game, while Arizona is allowing 17.5 points per game, which will help the under cash as this seems like a 20-17 game here.
Take the under.
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