Cardinals vs. 49ers Prediction, Odds, Spread, Injuries, Trends for NFL Week 3

Iain MacMillan | Sep 16, 2025

The 49ers host the Cardinals in NFL Week 3 action. / Stephen Lew-Imagn Images

The Arizona Cardinals and San Francisco 49ers are both 2-0 to start the season. Both teams were in danger of losing in both games, but ultimately came out on top.

Mac Jones will be making his second start in place of Brock Purdy, who is still recovering from a toe and shoulder injury. This will be the 49ers' first home game after playing in Seattle and New Orleans in their first two weeks.

Let's take a look at the odds and my best bet for this NFC West showdown.

Cardinals vs. 49ers Odds, Spread, and Total

Odds via DraftKings Sportsbook

Spread

• Cardinals +1.5 (-110)
• 49ers -1.5 (-110)

Moneyline

• Cardinals +114
• 49ers -135

Total

• OVER 44.5 (-105)
• UNDER 44.5 (-115)

Cardinals vs. 49ers How to Watch

• Date: Sunday, Sept 21
• Game Time: 4:25 pm ET
• Venue: Levi's Stadium
• How to Watch (TV): FOX
• Cardinals Record: 2-0
• 49ers Record: 2-0

Cardinals vs. 49ers Betting Trends

• Cardinals are 9-4 ATS in their last 13 games
• The OVER is 5-2 in the Cardinals' last seven games
• The UNDER is 4-1 in the Cardinals' last five road games
• Cardinals are 4-16 straight up in their last 20 games vs. NFC West opponents
• 49ers are 3-8 ATS in their last 11 games
• The OVER is 4-1 in the 49ers' last five games
• The OVER is 6-1 in the last seven meetings between these two teams
• 49ers are 4-12 ATS in their last 16 home games

Cardinals vs. 49ers Injury Reports

Cardinals Injury Report

• Cody Simon, LB - Questionable
• Tip Reiman, TE - Questionable
• Will Hernandez, G - Questionable
• Will Johnson, CB - Questionable
• Garrett Williams, CB - Questionable

49ers Injury Report

• Brock Purdy, QB - Out
• Siran Neal, CB - Questionable
• Ben Bartch, CB - Questionable
• Spencer Burford, OT - Questionable
• Jauan Jennings, WR - Questionable

Cardinals vs. 49ers Key Player to Watch

• Christian McCaffrey, RB - San Francisco 49ers

Lost in the shuffle with the 49ers so far this season is the fact that Christian McCaffrey seems to be healthy. He has struggled to move the ball effectively on the ground so far, averaging 3.5 yards per carry, but he's been a weapon through the air, hauling in 15 receptions for 125 yards. If he can stay healthy and Purdy can come back in a few weeks, the 49ers are going to be a force to be reckoned with when they hit their stride.

Cardinals vs. 49ers Prediction and Pick

In this week's edition of the Road to 272 Bets, I broke down why I'm going to back the 49ers as small favorites:

Mac Jones looked solid in his first start for the 49ers in place of Brock Purdy. He currently ranks 15th in the league in EPA+CPOE, which is above the likes of Kyler Murray and Sam Darnold. Sure, he's not elite or a top 10 quarterback, but he's good enough to lean on other aspects of the team to get the win.

Before you rush to bet on the Cardinals in this spot, let's remember they played the New Orleans Saints and Carolina Panthers in the first two weeks, which are two of the worst teams in the NFL, and they didn't look ultra-impressive in either of them.

Pick: 49ers -1.5 (-110) via DraftKings

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You can check out all of Iain's bets here!