New York Giants vs. San Francisco 49ers: Prediction, Best Bets, Odds, Depth Charts (9/21/23)

With these two teams off to drastically different starts, the New York Giants will visit the San Francisco 49ers on Thursday Night Football (9/21/23). Get Giants vs. 49ers odds, predictions, and best bets below as our best bet is 49ers -10.5.

New York Giants vs. San Francisco 49ers Prediction & Best Bet

It’s been a truly ugly start to the season for the New York Giants, and it could’ve been even worse if not for a strong finish on Sunday. After an utterly humiliating 40-0 home loss against their bitter rival Dallas Cowboys on opening day, the Giants found themselves down 20-0 to the openly-tanking Cardinals, capping off the worst six quarters of football you might ever see a team play.

Credit where credit’s due, they dusted themselves off and completed a really nice comeback against the Cardinals to win 31-28, but going down that badly against a team of Arizona’s caliber raises enormous red flags. To make matters worse, superstar back Saquon Barkley has been ruled out, leaving an already challenged offense without by far their best weapon.

By contrast, things have been great for the San Francisco 49ers so far. After coming a game away from reaching the Super Bowl for the second consecutive year, the Niners look poised to take the next step and make it to the big game this year, with their ever-crushing defense and an absolutely lethal offense. Based around NFL-best running back Christian McCaffrey and the ground game, the Niners attack has also enjoyed a second-year boost from QB Brock Purdy, who looks significantly improved thus far after offseason elbow surgery.

I’m never going to be particularly excited about laying more than 10 points with a Thursday night favorite, but the short week shouldn’t matter. This Giants team has looked completely lost to start the year, and going up against a team of this caliber without Barkley, it’s hard to imagine them keeping up. The total is also a tough play, as it’s hard to know if the G-men will contribute very much or at all to that number, and if not, how long the Niners will even be pushing for the end zone before they prioritize rest.

New York Giants vs. San Francisco 49ers Prediction & Best Bet: 49ers -10.5

New York Giants vs. San Francisco 49ers Betting Odds

The 49ers are 10.5 point favorites, with -110 odds on either side of that spread. With the total set at 45, there’s also -110 odds to take either side of that line.

New York Giants vs. San Francisco 49ers Key Injuries

The Giants have been hit hard by injuries already with star running back Saquon Barkley out, and tackle Andrew Thomas banged up. For the Niners, wideout Brandon Aiyuk is questionable after an awesome opening day.

New York Giants vs. San Francisco 49ers Key Matchups

With Saquon Barkley out, the Giants will need to find new ways to generate offense, while also working to slow down San Francisco’s explosive ground game. Let’s take a look at some positional matchups that could be key in these pursuits.

49ers Offensive Line vs. Giants Front Seven

In order to stay in this game, the Giants will absolutely have to force Purdy to beat them with his arm. If the Niners are allowed to run the ball the way they like to do, they’ll control the game and walk away with an easy win. That being said, forcing the Niners to the air isn’t the whole job, as Purdy has thrown the ball well to start the year; the Giants will need to pressure him, as he completed fewer than half of his passes under pressure last season. This might be a doable task, as outside of Trent Williams, the Niners’ offensive line has looked extremely mortal, with no other starter grading above 60.5 so far in PFF’s system.

That being said, the Giants don’t have a ton of weapons with which to accomplish these missions. Dexter Lawrence has been excellent in both pass rush and run defense to start the year, but other than Leonard Williams in specifically the former category, nobody has been particularly helpful in New York’s front seven. Especially when it comes to the run game, they’ll need more out of linebackers Bobby Okereke and Micah McFadden, and a year-two jump from Kayvon Thibodeaux would be huge, but the Oregon alum has shown just the opposite thus far.

Giants Skill Players vs. 49ers Defense

Barkley going down is a huge problem for the Giants, who have only seen other running backs produce 19 rushing yards thus far, compared to 114 from the Penn State superstar. That being said, Daniel Jones has run for 102 of his own yards already, and will likely have to shoulder even more of the load with his top weapon out. Matt Breida is the next back up, and will also pick up more touches of course, but the real answer might be being more pass-heavy. Offseason addition tight end Darren Waller is the team’s receiving leader thus far, while rookie Jalin Hyatt is up next, as newcomers have really led a group that was completely anemic last year.

The Niners defense had some questions coming into the year, but through two games, has looked like a superstar, championship-caliber unit once again. Nick Bosa looks like a DPOY candidate after signing an enormous extension, and while he’s the headliner, he’s far from alone. Javon Kinlaw, Drake Jackson, Arik Armstead and Javon Hargrave round out an incredibly deep defensive line that will make the Giants rushers’ lives a real challenge. Linebackers Fred Warner and Dre Greenlaw have had a slow start to the year, but remain a talented and seasoned duo that help in all facets of the game. The secondary is probably the weakest level of this defense, but with the likes of Talanoa Hufanga at safety and Charvarius Ward at corner, they should be able to handle a makeshift Giants receiving corps.

New York Giants Depth Chart

QB: Daniel Jones
RB1: Saquon Barkley
RB2: Matt Breida
LWR: Isaiah Hodgins
Darius Slayton

SWR: Sterling Shepard
TE1: Darren Waller

San Francisco 49ers Depth Chart

QB: Brock Purdy
RB1: Christian McCaffrey
RB2: Elijah Mitchell
LWR: Brandon Aiyuk
RWR: Deebo Samuel
SWR: Jauan Jennings
TE1: George Kittle

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From starting my own blog in Middle School, to working on a friend’s in college, and finally joining the Lineups team this year, I’ve been writing about sports for over a decade and betting on them as long as I’ve been legally able. I graduated from the University of Michigan last year, where I took sports journalism classes alongside my business major. Having played and watched sports for almost my whole life, I aim to provide insight and entertainment, as well as profitable picks, in my writing about professional and collegiate leagues.

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