San Francisco 49ers vs. New Orleans Saints, Picks and Prediction, Sunday, September 14, 2025

It’s an NFC matchup in the Big Easy on Sunday, Sept. 14. Read our San Francisco 49ers vs New Orleans Saints prediction along with our other NFL Picks! The 49ers are 1-0 and came away with a close win over Seattle in Week 1. Injury concerns are starting to pile for San Francisco, especially at key positions. The Saints are 0-1 after a one-possession loss to Arizona to start their season. They will look to bounce back against another NFC West opponent. These two teams will meet face-off with kick-off set for 1 P.M. EST.

Injuries are the big story for San Francisco this week

San Francisco is 1-0 to start the new season. Expectations are high for the 49ers once again this year as they look to claim the division and push for a deep playoff run. But, they have run into an early-season problem with injuries beginning to pile up.

In their last game, the 49ers defeated Seattle 17-13 on Sunday, Sept. 7. Seattle led 10-7 at halftime, but the 49ers were able to score 10 points in the fourth quarter to seal the win. Quarterback Brock Purdy threw a 4-yard touchdown pass to Jake Tonges with 1:34 left to give them the victory.

Purdy threw for 277 yards on 26-for-35 passing. He finished with two touchdowns and two interceptions. Christian McCaffrey looked solid as he rushed for 69 yards on 22 carries. It was a big game for wide receiver Ricky Pearsall, who caught four passes for 108 yards.

San Francisco’s defense was clutch in big situations during the game. They forced Seattle to go 3-for-10 on third down as the Seahawks finished with just 230 yards of offense. The 49ers turned the ball over twice, too. Fred Warner led the team with eight tackles, while it was a big game from Nick Bosa with one sack and three tackles for a loss.

Purdy is most likely to miss this game against the Saints. The quarterback hurt his toe on a rushing play in the second quarter. It would be a crushing blow that could sit the Iowa State alum out for not just this week, but multiple weeks.

"There's still a chance he could miss next game," Shanahan said. "We're not sure. We'll see how the toe heals. It's kind of week-to-week right now, but he's getting better. Had a good rehab day today and hopefully we'll have some better luck next week."

In Purdy’s place, quarterback Mac Jones will get the start for San Francisco. This is Jones’ first season with the 49ers. Last year, he played in 10 games for the Jaguars as Trevor Lawrence’s back-up. Prior to that, he was supposed to be the new franchise quarterback before the Patriots, but it didn’t pan out after three seasons. With the Jaguars, Jones threw for 1,672 yards and completed 65% of his passes along with eight touchdowns and eight interceptions.

As of Thursday, wide receiver Juan Jennings and Purdy did not participate. Wide receiver Jordan Watkins, running back Jordan James, defensive lineman Yetur Gross-Matos, and offensive lineman Ben Bartch were limited in practice.

The 49ers covered the spread as a 1-point favorite on the road in Seattle last week. The total was set at 43.5 and the under hit in the Week 1 game. Last year, the 49ers were 1-7 against the spread when they played on the road.

Kellen Moore era is underway for New Orleans

The Saints are 0-1 to begin the 2025 season. New Orleans fans saw their look Saints team in the opening game of the season. It was the first game of the year for new head coach Kellen Moore. There were some good things, but there was still a lot to be desired from a squad that is expected to be near the bottom of the standings this season.

In their opening game of the season, New Orleans lost 20-13 to the Cardinals on Sunday, Sept. 7. The Saints held an early lead to the game when running back Alvin Kamara rushed for an 18-yard touchdown to give the Saints a 7-3 advantage. The Saints would tie the game at 10 apiece with 4:58 left in the first half before the Cardinals would score 10 unanswered points. A late field goal cut the lead, but penalties were crucial to the Saints’ loss. They finished with 13 penalties for 89 yards.

Quarterback Spencer Rattler threw for 214 yards on 27-for-46 passing. He did not throw a touchdown while also not turning the ball over. Kamara led the rushing attack with 45 yards on 11 carries. Juwan Johnson was the top receiver with 76 yards on eight catches.

The defense for the Saints secured five sacks, which were key in keeping the game close. Pete Werner finished with a team-high nine tackles and one sack. Carl Grandson and Cameron Jordan each finished with 1.5 sacks.

“Good battle today,” Moore said after the loss to Arizona. “It certainly looked there like a moment where we had it. I thought our guys played with really good effort. The lesson for us is, ‘You can’t beat yourself.’ Thirteen penalties, we have to clean that up.”

As of Friday, defensive end Chase Young, offensive lineman Trevor Penning and safety Julian Blackmon are out for the game. Tackle Tallies Fuaga is questionable for the outing.

The Saints are 0-1 against the spread as they did not cover as six-point underdogs to the Cardinals at home in Week 1. The total was set at 44.5 and the under hit in the game.

San Francisco 49ers vs New Orleans Saints Pick

Spread Pick for San Francisco 49ers vs New Orleans Saints

• San Francisco 49ers -3.5 (5 units) 

The Saints were 6-point underdogs last week, and I think this line would be very similar if Brock Purdy were starting for San Francisco. Alas, he is not due to an injury and Mac Jones will get the start. I am still confident in Jones and this San Francisco offense. He’s a capable back-up, and in a Kyle Shanahan offense, there shouldn't be a step backwards for this time. Jones showed that he was capable last year with the Jaguars, and in this game, he will be going up against a poor defense in the Saints.

New Orleans was never expected to have a good defense this year and Arizona struggled to end drives in points last week. I am not sold on this New Orleans team, especially with Spencer Rattler at quarterback. He can hit the check-down pass, but he won’t be able to score enough touchdowns to lead to an upset win. Injuries have this line down, but remember, this roster is still strong for San Francisco as they go up against a Saints team bound for a top-five pick in next year’s draft.

Take the 49ers to cover. 

 

Over/Under Pick for San Francisco 49ers vs New Orleans Saints

• Under 40.5 (5 units)

Spencer Rattler would most likely be a backup quarterback in any other organization besides New Orleans. This means this game is truly a battle of second-string signal callers in Rattler and Mac Jones. It’s difficult to see based on years of data that either of these two quarterbacks can lead a team in a high-scoring game. The pass rush for both teams was strong last week, too. This will be a game settled by field goals rather than touchdowns.

Take the under on Sunday.