San Francisco 49ers vs Arizona Cardinals Prediction: Can Underdog Arizona Cardinals pull an upset repetition of last year?

San Francisco 49ers vs Arizona Cardinals: Prediction for the match on September 21, 2025

Two unbeaten rivals collide in Week 3. The Arizona Cardinals, also 2-0, head to the Bay Area to face the San Francisco 49ers. San Francisco knows how to adapt. Arizona, meanwhile, is looking to prove its hot start is no fluke. Here at Telecomasia, we will preview this game and offer the best betting opportunities.

San Francisco 49ers: Form and Statistics

San Francisco opened the season strong, covering the spread in every game. They are also perfect ATS when favored by 2.5 points or more. One of their two games has hit the over. Week 2 brought drama. With Brock Purdy sidelined, the 49ers turned to Mac Jones. The former Patriots starter stepped in and delivered. He threw for 279 yards, three touchdowns, and no picks, completing 67% of his passes in a 26-21 road win over the Saints.Christian McCaffrey didn’t dominate the stat sheet, but he stayed effective. He rushed 13 times for 55 yards, averaging 4.2 per carry. Across two games, he has 124 rushing yards with no scores, averaging 62 per game and 3.5 per attempt. His impact through the air has been bigger—15 catches on 17 targets for 125 yards and a touchdown. Now, San Francisco returns home for the first time this season, preparing for a tough divisional test with both quarterbacks and their star running back in the spotlight.

San Francisco 49ers: Team News

Purdy, before his injury, also showed flashes. He posted 277 yards with two touchdowns and two interceptions, completing 74% of his throws and averaging nearly eight yards per attempt.

Arizona Cardinals: Form and Statistics

The Cardinals have won their first two games of the season by a small amount. They beat the Panthers by a score of 27-22 in Week 2. A late sack from veteran Calais Campbell sealed the deal and ended Carolina's hopes of coming back. Kyler Murray has been on point. He has thrown for 383 yards, three touchdowns, and one pick. He completes more than 70% of his passes and throws for an average of 191 yards per game, which is 7.1 yards per attempt. He has also run for 70 yards, which is third on the team. Murray led an offense that averaged 6.1 yards per play against Carolina. The defense has come through when it mattered most. Campbell has two sacks, two tackles for loss, and ten tackles in just two games, making him the best player on the team. Mack Wilson, a linebacker, has made 16 tackles and broken up two passes. Budda Baker has 18 tackles and one stop behind the line. Baron Browning has helped out with a sack, two tackles for loss, six tackles, and a timely interception. This season, Arizona has only covered the spread once. One of their two games has gone over. This will be the first time they line up as underdogs. They now have to play a tough game against division rival San Francisco, a team they beat twice last season.

Arizona Cardinals: Team News

James Conner has 73 rushing yards and a touchdown on the ground in two games, which is an average of 36.5 yards per game. He has also caught five passes for 23 yards and another touchdown. Marvin Harrison Jr. is doing well in the air. He has caught seven passes for 98 yards and a touchdown on 11 targets. So far, tight end Trey McBride has been Murray's most reliable target, catching 12 passes for 139 yards on 16 attempts.

San Francisco 49ers vs Arizona Cardinals Betting Tips & Odds

• San Francisco has taken three of the last five meetings with Arizona. In that span, the 49ers scored 165 points while giving up 129.
• This season, they remain unbeaten against the spread. They were favored by at least 1.5 points twice, and covered both times. As moneyline favorites, they played two games and won them all. Their matchups have gone over the total once in two tries. The odds give them a 56.5% chance to win this contest.
• Arizona’s story is different. They have covered the spread once in two games. Their matchups also went over once. This will be their first outing as underdogs. The moneyline gives them a 47.6% shot at victory.

San Francisco 49ers vs Arizona Cardinals Match Prediction 21st September 2025

The stage shifts to the Bay, where the 49ers are 2.5-point favorites against the Cardinals. But there’s a cloud of uncertainty at quarterback. Brock Purdy is unlikely to play, leaving Mac Jones in line for another start. He looked solid last week, but the line tells its own story. The public leans heavy on San Francisco, and that’s where caution comes in. Arizona has quietly taken care of business. They haven’t crushed anyone, but they’ve closed out games. That spread shows Vegas respects them. Still, context matters. The Cardinals’ first two opponents—the Saints and Panthers—weren’t exactly powerhouses. The 49ers, on the other hand, have weathered injuries and kept winning. That resilience counts. So here’s the call: expect a tight battle in San Francisco’s home opener at Levi’s Stadium. The Niners should edge it out, but don’t be surprised if the Cardinals make it a fight.

Our match prediction is -2.5 Handicap San Francisco 49ers with odds at 1.83 on the 1Xbet bookmaker.

Our betting tip is Over 45.5 Total with odds at 1.91 on the Bet365 bookmaker.

Our final match prediction is San Francisco 49ers to win with odds at 1.75 on the Betway bookmaker.