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Christian McCaffrey #23 of the San Francisco 49ers warms up as we look at our best Giants-49ers predictions
Christian McCaffrey #23 of the San Francisco 49ers warms up before the game against the Los Angeles Rams at SoFi Stadium on September 17, 2023 in Inglewood, California. Photo by Sean M. Haffey/Getty Images via AFP.

As the New York Giants prep to take on the San Francisco 49ers, we're breaking down the best NFL odds with our Giants-49ers predictions for Thursday Night Football.

The New York Giants appeared to be on the verge of a 0-2 start, but they equaled a franchise record with their largest comeback (21 points) to defeat the Arizona Cardinals. However, the Giants are now facing another challenging situation on Thursday as they must deal with the absence of running back Saquon Barkley in this game, and they are pitted against one of the NFL's top-performing teams, the San Francisco 49ers.

The 49ers extended their streak of dominance over the Los Angeles Rams, securing their ninth consecutive regular-season victory against them. This win also marks their 12th consecutive regular-season victory overall, a feat they haven't accomplished since 1989-90.

To help start your NFL predictions for Week 3, here is our best Giants-49ers prediction and Thursday Night Football best bets, and don't miss our Giants vs. 49ers player props (odds via our best NFL betting sites; pick confidence is based on a 1-to-5-star scale).

Giants vs. 49ers prediction: Thursday Night Football

49ers -9.5 (-110 via FanDuel, Caesars) ⭐⭐⭐

The Giants had been outscored 60-0 through a game-and-a-half and were held scoreless across their first six quarters of a season for the first time since 1934. Thus, while their comeback from being 20-0 down at halftime and 28-7 in the third quarter against the Cardinals helped to cool off criticism for a week, significant problems persist.

Barkley has been ruled out for Thursday's game, which is bad news for quarterback Daniel Jones, who played 34 games with Barkley entering 2023-24 and had produced a 44:17 touchdown-to-interception ratio while averaging 230 passing yards per game. Jones has posted a 16:17 TD:INT ratio while averaging 198 passing yards per game across 19 contests without Barkley.

Furthermore, the Giants registered a +40.1 offensive EPA, averaged 5.4 yards per play, and 4.7 yards per rush with Barkley healthy and active over the last five seasons entering 2023-24. Without Barkley, those numbers plummet to a -126.9 offensive EPA, 5.0 yards per play, and 4.2 yards per rush.

Jones made history during the second half against Arizona, as Boomer Esiason explained. However, it's unreasonable to think the team can put that much on his shoulders again with a one-dimensional offense and expect to compete against a team as explosive as the 49ers. Christian McCaffrey has scored a touchdown in 11 straight games (including playoffs), and while Brock Purdy's streak of six consecutive outings with two-plus passing touchdowns and a 95.0 or better passer rating was snapped in Week 2, he still posted an impressive 93.1 passer rating and played turnover-free football. Purdy is the eighth quarterback since 1950 to win his first seven regular-season starts.

It's therefore only a matter of how much San Francisco will win by on Thursday, and the 49ers are the fourth-most profitable ATS team over the last two seasons (26-15-1). We're comfortable laying less than double digits against a banged-up Giants team.

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Giants vs. 49ers best odds

FanDuel, Caesars (-110)


Seeing our best live betting sites on either side of the key betting number of -10 is interesting. 49ers backers get an easy choice of heading to FanDuel or Caesars, where they don't need to pursue alternate point spreads to get off of or move from under the key figure.

Purdy is 7-2-1 ATS across 10 career starts, but teams at home on Thursday Night Football are 24-38 ATS since 2019.

Giants vs. 49ers odds for Thursday Night Football

Giants vs. 49ers odds analysis

The lookahead line for this game was 49ers -6 in late August, but New York’s issues through the first two weeks and Barkley’s injury status made it balloon quickly. FanDuel and Caesars arrived at -10.5 late Monday morning before Giants backers scooped that number up quickly, driving the line down considerably. No shop has reached -11 or higher yet.

FanDuel is the only one of our best sportsbooks offering a total of 44.5, as every other book is at 45. DraftKings was the only shop to reach 45.5 on Sunday night, but it's since settled in with the majority of the market at 45 throughout Monday. There's good early two-way betting action on the total, with a slight percentage (54%) in favor of the Under.

Thursday Night Football game info

  • When: Thursday, Sept. 21 at 8:15 p.m. ET
  • Where: Levi’s Stadium, Santa Clara, CA
  • How to watch: Prime Video
  • Weather: 77 degrees, 6% chance of precipitation, wind 11-mph southwesterly winds

Giants-49ers prediction made 9/18/23 at 11:33 a.m. ET

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