49ers vs. Saints Prediction, Odds, Spread, Injuries, Trends for NFL Week 2

Iain MacMillan | Sep 9, 2025

The 49ers are road favorites against the Saints in NFL Week 2. / Steven Bisig-Imagn Images

The San Francisco 49ers were hoping to move on from their disastrous 2024 season, but things largely picked up right where they left off. Missed field goals, missed opportunities, and injuries to key players were the story of the 49ers' Week 1 game against the Seahawks. Yes, the 49ers got the win, but at what cost?

They'll limp to New Orleans in Week 2 when they take on the Saints, who fell short against the Arizona Cardinals in Week 1.

Let's dive into the odds and my best bet for this NFC showdown.

49ers vs. Saints Odds, Spread, and Total

Odds via BetMGM Sportsbook

Spread

• 49ers -4.5 (-110)
• Saints +4.5 (-110)

Moneyline

• 49ers -225
• Saints +185

Total

• OVER 42.5 (-110)
• UNDER 42.5 (-110)

49ers vs. Saints How to Watch

• Date: Sunday, Sept. 14
• Game Time: 1:00 pm ET
• Venue: Caesars Superdome
• How to Watch (TV): FOX
• 49ers Record: 1-0
• Saints Record: 0-1

49ers vs. Saints Betting Trends

• 49ers are 2-8 ATS in their last 10 games
• The OVER is 4-2 in the 49ers' last six games
• 49ers are 6-2-1 ATS in their last nine games vs. Saints
• 49ers are 1-5 ATS in their last six road games
• 49ers are 6-1 straight up in their last seven games vs. NFC South opponents
• Saints are 4-10 ATS in their last 14 games
• The UNDER is 6-1 in the Saints' last seven games
• Saints are 2-10-1 ATS in their last 13 games played in Week 2

49ers vs. Saints Injury Reports

49ers Injury Report

• George Kittle, TE - Out
• Jauan Jennings, WR - Questionable
• Jordan Watkins, WR - Questionable
• Jordan James, RB - Questionable
• Brock Purdy, QB - Questionable

Saints Injury Report

• Chase Young, DE - Questionable
• Trevor Penning, OT - Questionable
• Jordan Howden, S - Questionable
• Julian Blackmon, S - Questionable
• Taliese Guaga, OT - Questionable

49ers vs. Saints Key Player to Watch

• Christian McCaffrey, RB - San Francisco 49ers

If Brock Purdy isn't able to suit up on Sunday, the 49ers are going to lean heavily on Christian McCaffrey. The good news about McCaffrey is that he was healthy enough to suit up in Week 1. The bad news is he averaged just 3.1 yards on 22 carries. He made up for it in the passing game, hauling in nine receptions for 73 yards, but he needs to be able to move the ball on the ground more effectively moving forward.

49ers vs. Saints Prediction and Pick

In this week's edition of the Road to 272 Bets, I broke down why, despite the injuries, I still trust the 49ers to win and cover in this spot:

The injuries for the San Francisco 49ers are far from ideal, and I unfortunately placed this bet before the news about Brock Purdy was released. Still, I'm going to trust this San Francisco team to get the job done against a Saints team that I'm still convinced is the worst in the league. Spencer Rattler ranked 26th amongst all quarterbacks in Week 1 in EPA+CPOE composite, which is exactly what we expected from him.

No matter who is playing at quarterback or tight end for San Francisco, the team is deep enough and coached well enough that I still expect them to cruise past the Saints in New Orleans.

Pick: 49ers -4.5 (-110) via BetMGM

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