As Week 2 of the 2025 NFL season kicks off, the San Francisco 49ers head to New Orleans to take on the Saints in a matchup that could highlight key mismatches on both sides. In this 49ers vs Saints betting prediction, we break down how San Francisco’s depth, coaching, and offensive weapons stack up against a Saints team still searching for consistency. From quarterback play to running game advantages and defensive matchups, this preview gives bettors a clear picture of which side is most likely to cover the spread.
Game Info:
- Kickoff: Sunday, September 14, 2025 – 1:00 PM ET
- Location: Caesars Superdome, New Orleans, LA
- TV: FOX
- Spread: 49ers -3
- Moneyline: 49ers -165 | Saints +140
- Over/Under: 40.5
Betting Preview
The San Francisco 49ers enter Week 2 at 1-0, coming off a solid opener. The New Orleans Saints are 0-1 and still searching for consistency. This game features mismatches that should favor San Francisco, particularly in coaching adjustments, depth, and defensive execution.
Quarterback Play
Brock Purdy is sidelined with a turf toe, allowing Mac Jones to start. While Jones has had an inconsistent career, San Francisco’s system is designed to support him with quick passes and motion to neutralize pressure. The Saints have an aggressive pass rush, but the 49ers’ line depth gives them the edge.
Running Game
Christian McCaffrey is central to the offense. After a 142-yard performance in Week 1, he faces a Saints defense that struggled against the run. Controlling McCaffrey is critical for New Orleans to stay competitive, but San Francisco is likely to lean heavily on their workhorse back.
Defensive Edge
The 49ers’ front seven can disrupt both run and pass plays. The Saints’ offense is still finding its rhythm, which could lead to mistakes under pressure. Shanahan will look to exploit mismatches both at the line and in coverage.
Coaching Matchup
Kyle Shanahan is a master of scheming around injuries and exploiting weaknesses. The Saints’ staff is talented but may struggle against the 49ers’ adaptive game plan.
Betting Insights
The 49ers -3 is likely to cover, given the clear mismatches, depth, and coaching advantage. Public betting trends and line movement can be viewed here: NFL Public Betting Chart. For current odds and to place bets, visit Bovada.lv.
Prediction: 49ers 24, Saints 17