Undefeated NFC West rivals square off in Week 3 NFL action as the San Francisco 49ers host the Arizona Cardinals. Kyler Murray and the Cardinals face their first division rival of the season after kicking off the 2025 campaign with wins against the New Orleans Saints and the Carolina Panthers. The 49ers head into their home opener with gritty wins against the Seattle Seahawks and the Saints, but quarterback Brock Purdy (shoulder/toe) is not expected to be under center.
Kickoff from Levi’s Stadium is set for 4:25 p.m. ET. San Francisco is a 1.5-point favorite in the latest Cardinals vs. 49ers odds from SportsLine consensus, while the over/under for total points scored is 44.5. The 49ers are -125 money line favorites (risk $125 to win $100), while the Cardinals are +106 underdogs. Before making any 49ers vs. Cardinals picks, make sure you check out the picks from the SportsLine Projection Model.
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Where to watch Cardinals vs. 49ers on Sunday
When: Sunday, Sept. 21
Time: 4:25 p.m. ET
TV: FOX
Stream: Fubo
Follow along: CBS Sports App
49ers vs. Cardinals betting preview
Odds: 49ers -1.5, over/under 44.5
The Cardinals didn’t blow out either of their opponents in Weeks 1 and 2, but Murray has been solid with a 70.4% completion rate and a 3-1 TD-INT ratio. He’ll face his toughest test of the early season against the 49ers defense, although he and Marvin Harrison Jr. connected for seven catches for 99 yards and one touchdown against San Francisco last season. One concern is the Arizona defense, which is dealing with multiple injuries.
That could spell trouble against a 49ers offense that played well in Week 2 with Purdy and George Kittle sidelined. Backup quarterback Mac Jones impressed with three touchdowns and 279 passing yards against New Orleans, and Christian McCaffrey played a hybrid role to make up for the depleted receiving corps. San Francisco’s defense has allowed 17 points per game to start the season, allowing 268.5 average yards through two games.
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Model’s Cardinals vs. 49ers prediction, picks
The health of both of these teams will play a huge role in Sunday’s matchup. The 49ers don’t appear worried that Purdy likely can’t play since Jones had a strong showing in Week 2. Arizona’s losses on defense, on the other hand, are harder to make up for. The SportsLine model projects San Francisco will cover the spread in 55% of simulations.
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