by Rod Pearson
Friday, Sep 25, 2026
Game Time: 4:05 pm ET, Sunday, September 27, 2026
Venue: Levi's Stadium, Santa Clara, CA
Where to Watch: FOX
Opening Odds at USA Sportsbooks
DraftKings: Point Spread: Cardinals +8.5, 49ers -8.5; Over/Under: 47.5 points
Bet365: Point Spread: Cardinals +8.5, 49ers -8.5; Over/Under: 48 points
BetMGM: Point Spread: Cardinals +8.5, 49ers -8.5; Over/Under: 48 points
Season Record
Arizona Cardinals: 1-1 (3rd place, NFC West)
San Francisco 49ers: 2-0 (1st place, NFC West)
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Arizona Cardinals: lost their last game at home against the Seattle Seahawks 31-7.
San Francisco 49ers: won their last game at home against the Miami Dolphins 35-13.
Arizona Cardinals vs San Francisco 49ers Preview and Analysis
The Cardinals are entering this game with a 1-1 record overall and they have a 0-1 record in their divisional games too. They are 0-1 in their home games, 1-0 in their road games, and they are also 0-0 in their neutral site games this season, but they will be on the road for this game. They lost their last game against the Seattle Seahawks 31-7. Jacoby Brissett was the starting QB and he completed 17/28 passes for 95 passing yards, 1 touchdown, and 1 interception. Jeremiyah Love led the team in rushing yards with 29. Trey McBride led the receivers with 41 receiving yards on 8 receptions and 1 TD. Budda Baker led the defense in that game with 11 solo tackles while Budda Baker led the defense in sacks with 1. No one on the defense came away with an interception for them in that one.
The 49ers are entering this game with a 2-0 record overall and they have a 1-0 record in their divisional games too. They are 1-0 in their home games, 0-0 in their road games, and they are also 1-0 in their neutral site games this season, but they will be at home for this game. They won their last game against the Miami Dolphins 35-13. Brock Purdy was the starting QB and he completed 20/22 passes for 287 passing yards, 2 touchdowns, and 0 interceptions. Brock Purdy led the team in rushing yards with 30 and 1 TD. George Kittle led the receivers with 80 receiving yards on 4 receptions and 1 TD. Ji'Ayir Brown led the defense in that game with 13 solo tackles while Marques Sigle, Keion White, and Romello Height each led the defense in sacks with 1. No one on the defense came away with an interception for them in that one.
Cardinals vs 49ers Prediction
The current betting odds have the 49ers listed as an 8.5 point favorite in this game according to Draftkings Sportsbook. The 49ers have looked great in their games this season with their 2-0 record overall so far. They have looked good on their home field too with their 1-0 home record this season. Meanwhile, the Cardinals haven't looked great in their games this season with their 1-1 record overall so far. They have been a good road team though with their 1-0 road record this year. The Cardinals were projected to be one of the worst teams in the NFL this season with the lowest win total for an NFL team in years, but they came out of the gate really strong with a 26-14 win over the Chargers. They are still in the 1st year of a new head coach though and they don't have a great team. That showed last week as they came back down to Earth, losing to the Seahawks 31-7. Their offense couldn't get anything going against that defense and now they will be facing another good defense on a 49ers team that looks like it can compete for the NFC West once again. The 49ers are coming off a 35-13 win over the Dolphins and that was after coming back from Australia where they destroyed the Super Bowl favorites, beating the Rams 27-7. The 49ers look like a contender again and if that Cardinals offense had trouble against the Seahawks last week, it isn't going to get any easier for them here. The Cardinals don't have a ton of talent on defense either and this 49ers offense has been rolling to start the season. The best way to place a bet here is on the 49ers to cover the spread in this game.
Cardinals 49ers Prediction: Our NFL Pick for Sunday, September 27, 2026 (4:05 pm ET start time) is 49ers 30 Cardinals 10.
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NFL Betting Trends
Arizona Cardinals: 10-5 ATS as a road underdog. 10-4 ATS in a road game where the total is between 42.5 and 49 points. 6-3 ATS on the road after 1 or more consecutive losses. 6-2 OVER after playing a division game. 6-1 OVER off a loss against a division rival.
San Francisco 49ers: 4-8 ATS in a home game where the total is greater than or equal to 45.5. 5-9 ATS versus division opponents. 3-8 ATS after scoring 30 points or more last game. 22-15 OVER in all games.
Key Injuries
Arizona Cardinals: M. Wilson Sr. (LB) Injured - Rest. J. Brissett (QB) Injured - Hip. R. Lopez (DL) Injured - Groin. M. Melton (CB) Injured - Toe. I. Seumalo (OG) Injured - Rest. J. Sweat (LB) Injured - Rest. D. Taylor-Demerson (S) Injured - Back. H. Froholdt (OG) Injured - Knee. G. Williams (CB) Injured - Achilles.
San Francisco 49ers: T. Williams (OT) Injured - Rest. C. McCaffrey (RB) Injured - Rest. D. Robinson (WR) Injured - Ankle. M. Evans (WR) Injured - Hip. D. Greenlaw (LB) Injured - Rest. N. Bosa (DL) Injured - Rest. R. Height (DL) Injured - Hand. J. Thompson Jr. (DL) Injured - Ankle.
Notable Quotes
“We're not going to hit the panic button, but when we play the best defense in ball, you've got to do all the little things right. We did not today.” - Mike LaFleur after his team’s loss against the Seahawks in their last game.
“That’s what I was real proud of the guys. That was the biggest challenge of this, just the human nature of what all went into Week 1 and the travel and everything and coming back after five days off. But we got a really cool team in terms of how much guys care about football how into it they are.” - Kyle Shanahan after his team’s win against the Dolphins in their last game.
Starting Lineups
Arizona Cardinals
WR Harrison Jr., Marvin
WR Wilson, Michael
WR Bourne, Kendrick
TE McBride, Trey
QB Brissett, Jacoby
RB Love, Jeremiyah
San Francisco 49ers
WR Evans, Mike
WR Hodge, Khadarel
WR Samuel Sr, Deebo
TE Kittle, George
QB Purdy, Brock
RB McCaffrey, Christian
FB Juszczyk, Kyle
Statistical Leaders
Arizona Cardinals
Passing: Jacoby Brissett (372)
Rushing: Tyler Allgeier (71)
Receiving: Trey McBride (136)
Touchdowns: Trey McBride (2)
San Francisco 49ers
Passing: Brock Purdy (492)
Rushing: Christian McCaffrey (91)
Receiving: Mike Evans (103)
Touchdowns: Christian McCaffrey (2)
Coaches:
Arizona Cardinals: Mike LaFleur (1st season)
San Francisco 49ers: Kyle Shanahan (10th season)
Rod Pearson
About the Author:
Rod Pearson has been a rabid sports fan his entire life. He grew up in Ontario, and was skilled in both hockey and baseball, and pitched in an elite baseball league for many years. In 2022, Rod decided to hang up his glove, so that he could write about the sports he loves -- but from a gambling perspective. Join Rod every day as he breaks down the games to find the best betting value.
