The San Francisco 49ers will host the Arizona Cardinals at Levi’s Stadium for a Week 3 showdown in the 2025 NFL season. Both teams enter the game with a 2-0 record, making this matchup an early test for dominance in the NFC West. With the game set to kick off at 4:25 PM on Sunday, September 21st, fans can catch the action on FOX.
Weather conditions in Santa Clara, CA, are expected to be ideal, with clear skies and mild temperatures, providing a perfect setting for outdoor football. The Cardinals, under the guidance of head coach Jonathan Gannon, have been impressive with victories over the Carolina Panthers and New Orleans Saints. Meanwhile, the 49ers, led by head coach Kyle Shanahan, have secured wins against the New Orleans Saints and Seattle Seahawks.
According to the consensus odds, the 49ers are slightly favored with a moneyline of -127, while the Cardinals have a moneyline of +107. The spread is narrow, with the 49ers at -1.5 and the Cardinals at +1.5. The total for the game is set at 44.0 points, indicating expectations for a closely contested game between two well-matched teams.
49ers vs Cardinals At a Glance
- Game Date & Time: Sunday, September 21, 2025 at 4:25 PM
- Location: Levi’s Stadium in Santa Clara, CA
- Weather Forecast: Clear sky with mild, calm conditions
- TV Channel: FOX
- Team Records: Both the Arizona Cardinals and San Francisco 49ers hold a 2-0 record this season
- Game Odds: 49ers are favored with a -127 moneyline and a -1.5 spread
San Francisco 49ers: Poised for Another Victory?
Offensive Dynamics
The San Francisco 49ers have exhibited a robust offensive performance with 4,234 passing yards, ranking 4th in the league. Their ability to move the ball through the air is evident, providing a solid foundation for their offensive strategy.
Their rushing game is also a key component, accumulating 2,163 yards and securing the 12th spot in league rankings. This balanced attack allows the 49ers to keep defenses on their toes and capitalize on various offensive opportunities.
Defensive Insights
Defensively, the 49ers have room for improvement, having allowed 436 points, placing them at 26th in the league. However, their ability to pressure opposing quarterbacks is noteworthy with 37 sacks, ranking 12th.
They have also demonstrated a knack for forcing turnovers, with 11 interceptions and 6 fumbles recovered, both ranking 9th. This opportunistic defense can be a game-changer, creating critical moments that swing momentum.
Recent Performances
In Week 2, the 49ers secured a 26-21 win against the New Orleans Saints. Mac Jones shined with 279 passing yards and 3 touchdowns, showcasing the team’s offensive depth.
Week 1 saw the 49ers win 17-13 against the Seattle Seahawks. Their defensive prowess was on display, allowing only 146 passing yards from Seattle, highlighting their ability to shut down opposing offenses.
Key Players to Watch
Christian McCaffrey has been a dual threat with 124 rushing yards and 15 receptions. His versatility is a major asset for the 49ers’ offensive schemes.
On defense, Fred Warner continues to lead with a solid 7 solo tackles and 4 assists in recent games. His presence on the field is crucial for the 49ers’ defensive stability.
Team Betting Trends
- O/U – After Loss (REG): 7-2 (77.8%)
- ATS – As Favorite (REG): 8-3 (72.7%)
- O/U – All Games (REG): 4-1 (80.0%)
- O/U – As Underdog (REG): 3-1 (75.0%)
- O/U – Away Games (REG): 3-1 (75.0%)
- ATS – After Win (REG): 3-1 (75.0%)
Arizona Cardinals Set to Challenge the 49ers: A Game Preview
Cardinals’ Offensive Performance
The Arizona Cardinals enter this game with a strong offensive unit, ranking 12th in scoring with 400 points in the 2024 regular season. Their passing game has been steady, accumulating 3,639 yards, placing them 18th in the league. On the ground, the Cardinals have excelled, rushing for 2,451 yards and securing the 7th spot in rushing yards.
First downs have come frequently for Arizona, with 356 total, ranking 8th. Their efficiency on third downs is also notable, converting 43% of attempts, again placing them 8th in the NFL. This balance between passing and rushing, combined with strong third-down performance, has been pivotal to their success.
Defensive Strengths and Areas to Watch
Defensively, the Cardinals have been solid, allowing 379 points, ranking them 14th in opponent scoring. Their pass rush has been effective, achieving 41 sacks and ranking 8th. The defense has also been opportunistic, securing 9 interceptions, ranking 11th.
Their ability to recover fumbles, with 8, is ranked 7th, showcasing their knack for forcing turnovers. However, they have allowed 5,823 opponent offensive yards, placing them 21st, indicating a potential vulnerability in yardage defense.
Key Players to Watch
Quarterback Kyler Murray is a focal point of the Cardinals’ offense, having thrown for 383 yards and 3 touchdowns over two games. His dual-threat capability with 35 rushing yards adds another dimension to their attack. Running back James Conner is another key player, with 73 rushing yards and 1 touchdown, contributing significantly to the ground game.
On the defensive side, Calais Campbell leads with 2 sacks, while safety Jalen Thompson has been pivotal in coverage with 6 solo tackles against the Panthers. These players are expected to play crucial roles against the 49ers.
Recent Performance and Injury Concerns
The Cardinals have started the season with two wins, defeating the Panthers 27-22 and the Saints 20-13. Despite these victories, the team faces several injury concerns. Key players like Will Hernandez and L.J. Collier are listed as questionable, while others like Justin Jones and Bilal Nichols are out, potentially impacting their depth.
Garrett Williams and Tip Reiman are also questionable, which could affect the defensive and offensive schemes. The team will need to manage these injuries carefully to maintain their early momentum.
Betting Trends
- O/U – Home Games (REG): Last 4 REG Games (2024–2025) → 4-0 (100.0%)
- SU – All Games (REG): Last 3 REG Games (2024–2025) → 3-0 (100.0%)
- SU – As Favorite (REG): Last 3 REG Games (2024–2025) → 3-0 (100.0%)
- SU – Home Games (REG): Last 3 REG Games (2024–2025) → 3-0 (100.0%)
- O/U – As Favorite (REG): Last 6 REG Games (2024–2025) → 5-1 (83.3%)
- O/U – All Games (REG): Last 7 REG Games (2024–2025) → 5-2 (71.4%)
- ATS – Home Games (REG): Last 7 REG Games (2024–2025) → 5-2 (71.4%)
- SU – After Win (REG): Last 7 REG Games (2024–2025) → 5-2 (71.4%)
- O/U – After Loss (REG): Last 4 REG Games (2024) → 3-1 (75.0%)
- ATS – All Games (REG): Last 3 REG Games (2024–2025) → 2-1 (66.7%)
- ATS – As Favorite (REG): Last 3 REG Games (2024–2025) → 2-1 (66.7%)
- O/U – After Win (REG): Last 3 REG Games (2024–2025) → 2-1 (66.7%)
- SU – After Loss (REG): Last 3 REG Games (2024) → 2-1 (66.7%)
- ATS – After Loss (REG): Last 3 REG Games (2024) → 2-1 (66.7%)
- SU – As Underdog (REG): Last 7 REG Games (2024) → 4-3 (57.1%)
- ATS – After Win (REG): Last 6 REG Games (2024–2025) → 3-3 (50.0%)
- SU – Away Games (REG): Last 8 REG Games (2024–2025) → 3-5 (37.5%)
- ATS – As Underdog (REG): Last 5 REG Games (2024) → 2-3 (40.0%)
- O/U – Away Games (REG): Last 6 REG Games (2024–2025) → 2-4 (33.3%)
- ATS – Away Games (REG): Last 3 REG Games (2024–2025) → 1-2 (33.3%)
49ers vs Cardinals Prediction: Over 44.0
The San Francisco 49ers and Arizona Cardinals both come into this game with a perfect 2-0 start to the season. These NFC West rivals have shown strong offensive capabilities, with the Cardinals scoring a total of 400 points last season and the 49ers close behind with 389. The recent head-to-head games often saw high scores, with several matchups surpassing the 44-point total.
San Francisco’s offense, ranked 4th in passing yards last season, is expected to challenge Arizona’s defense. Meanwhile, the Cardinals’ robust rushing attack, ranked 7th last season, will aim to exploit a 49ers defense that allowed 436 points, ranking 26th. These dynamics suggest a game that could easily exceed the 44-point total set by sportsbooks.
Notably, the 49ers have shown a tendency towards high-scoring games, with a 4-1 over/under record in their last five regular season games. Additionally, the Cardinals have demonstrated strong offensive performance in recent matchups against the 49ers. The favorable weather conditions at Levi’s Stadium will further support the potential for a high-scoring game.
Taking these factors into account, my prediction is that the total points scored will go over the 44-point mark. I project a final score where both teams effectively utilize their offensive strengths against the opposing defenses.
- 49ers vs Cardinals Prediction: Over 44.0
- 49ers vs Cardinals Score: 49ers 31 – Cardinals 27
