Cardinals vs 49ers Prediction 9/21/25 NFL Picks Today

In this article, we will formulate a Cardinals vs 49ers Prediction for this NFL Week 3 game on Sunday, September 21^st at the Levi’s Stadium. Let’s take a look at the prediction for this NFL matchup.

San Francisco 49ers Preview

San Francisco has a 2-0 record this season and is coming off a 26-21 road victory in New Orleans. Offensively, they average 21.5 points per game, which ranks 18th in the NFL. Defensively, they allow 17.0 points per game, which ranks 7th. San Francisco averages 364 total yards per game, with 98 rushing yards and 266 passing yards per game. They allow 268.5 total yards per game, 102.5 rushing and 166 passing yards per game.

Mac Jones and Brock Purdy share quarterback duties with Jones completing 26/39 passes for 279 yards and Purdy completing 26/35 passes for 277 yards. Christian McCaffrey leads the team in rushing yards, with 124, while Brian Robinson Jr. adds 53 rushing yards. Christian McCaffrey has a team-high 15 caught passes for a team-high 125 receiving yards, and has one touchdown. Ricky Pearsall has caught 8 passes for 164 yards.

Defensively, Fred Warner has a team-high 19 total tackles, 11 of them solo. Nick Bosa leads the 49ers in sacks, with two.

Arizona Cardinals Preview

Arizona has a 2-0 record this season and is coming off a 27-22 home victory over Carolina. Offensively, they average 23.5 points per game, which ranks 11th in the NFL. Defensively, they allow 17.5 points per game, which ranks 10th. Arizona averages 284.5 total yards per game, with 114 rushing yards and 170.5 passing yards per game. They allow 333.5 total yards per game, 78 rushing and 255.5 passing yards per game.

Kyler Murray leads the Cardinals with 38/54 completed passes and 341 total passing yards. He also adds 70 rushing yards. Trey Benson leads the team in rushing yards, with 83, while James Conner adds 73 rushing yards. Trey McBride has a team-high 12 caught passes for a team-high 139 receiving yards. Marvin Harrison Jr. has caught 7 passes for 98 yards, and has one touchdown.

Defensively, Budda Baker has a team-high 18 total tackles, 9 of them solo. Calais Campbell leads the Cardinals in sacks, with two. Baron Browning has one interception.

Arizona Cardinals @ San Francisco 49ers Betting Trends: Week 3

Why the San Francisco 49ers will win

• The Cardinals have lost each of their last eight games against opponents on a winning streak.
• The 49ers have won each of their last four home games in September.
• The favorites have covered the spread in each of the 49ers’ last four games.
• The Cardinals have failed to cover the spread in four of their last five Week 3 games against NFC opponents.
• The 49ers have won the first quarter in each of their last nine games in California.
• The 49ers have scored the first touchdown in each of their last six Sunday games as favorites.
• The Cardinals have lost the first half in 15 of their last 16 Week 3 road games.

Why the Arizona Cardinals will win

• The 49ers have lost each of their last seven Week 3 games against NFC West opponents.
• The road team has won seven of the Cardinals’ last eight Week 3 games.
• The 49ers have failed to cover the spread in each of their last nine home games following a win.
• The Cardinals have covered the spread in each of their last eight road games in September.
• The Cardinals have won the first quarter in three of their last four September games as underdogs.
• The Cardinals have scored the first touchdown in eight of their last nine Sunday games played on the West Coast.
• The 49ers have lost the first half in each of their last four Sunday games against teams that held a winning record.

Total Points Facts

• Each of the Cardinals’ last six September games as underdogs against NFC West opponents have gone UNDER the total points line.
• Eight of the 49ers’ last nine games against the Cardinals following a win have gone OVER the total points line.

San Francisco 49ers Player Prop Facts

• Brian Robinson has recorded 33+ rushing yards in each of his six previous appearances against NFC West opponents.
• Brian Robinson has recorded 43+ rushing and receiving yards in nine of his 10 previous appearances with his team as a home favorite against NFC opponents.
• Russell Gage has scored at least one touchdown in three of his last four appearances in home day games against teams with a winning record.
• Mac Jones has recorded 231+ passing yards in each of his five previous September home appearances.
• Ricky Pearsall has recorded 56+ receiving yards in each of the 49ers’ last four games.
• Mac Jones has recorded 22+ completions in each of his five previous September home appearances.
• Heading into Week 3, Fred Warner ranks T1st in the league for fumbles recovered (1) this season.

Arizona Cardinals Player Prop Facts

• James Conner has scored a touchdown in seven of the Cardinals’ last eight September games.
• Kyler Murray has recorded 260+ passing yards in each of the Cardinals’ last four games as underdogs.
• Trey McBride has recorded 65+ receiving yards in each of the Cardinals’ last seven games played on the West Coast.
• Kyler Murray has recorded 32+ rushing yards in each of the Cardinals’ last four road games.
• James Conner has recorded 89+ rushing and receiving yards in three of the Cardinals’ last four games as underdogs against NFC West opponents.
• Kyler Murray has recorded 21+ completions in each of his 10 previous September appearances with the Cardinals as underdogs.
• Heading into Week 3, James Conner ranks T1st amongst qualified players for catch rate (100.0%) this season.

Matchup/League Facts

• 49ers – three different players have recorded 60+ receiving yards in a game this season – equal-most in the NFL, heading into Week 3.
• 49ers – three different players have recorded 70+ receiving yards in a game this season – equal-most in the NFL, heading into Week 3.
• Heading into Week 3, the Cardinals rank T1st in the NFL in 4th down percentage (100.0%) this season.
• Heading into Week 3, the Cardinals rank T1st in the NFL in Q1 win percentage (100.0) this season.

Cardinals vs 49ers Prediction

The Cardinals won both meetings against the 49ers last season. At home by 47-24 and on the road by 24-23, covering the spread in both. The 49ers have won the four meetings before that, but the Cardinals are 3-2 in their last 5 trips to San Fran. Over is 6-1 in their last 7 meetings.

In this Cardinals vs 49ers Prediction, the 49ers are coming as -2.5-point home favorites, with the total set at 45 points. Both teams are undefeated in this young season, with the 49ers having covered the spread in both, and are playing their first game in front of their home crowd. Arizona’s only home win this season was against a weak New Orleans squad, and while both teams have similar offensive and defensive numbers, the 49ers are far better in yards for and against. The value lies with the home team in this matchup, so take the San Francisco 49ers and lay the -2.5 points at home.