San Francisco 49ers vs. New York Giants Prediction, Odds, Picks

The San Francisco 49ers (2-0) are considered favorites (-10.5) according to the bookmakers ahead of their game against the New York Giants (1-1) on September 21 starting at 8:15 PM ET, airing on Amazon Prime Video. 

The 49ers are looking to continue their showing as the cream of the crop in the NFC, if not the NFL. While the Giants are hoping to shore up their defense after allowing 68 points in their first two games. 

Here's everything you need from a betting perspective on the game between the Giants and 49ers from the point spread, moneyline, total over/under and an expert pick from Jason McIntyre.

49ers vs. Giants Odds & Betting Lines

49ers vs. Giants Prediction & Pick

• Pick ATS: San Francisco (-10.5) 
• Pick OU: Over (45.5) 
• Prediction: San Francisco 42 - New York 6

Pick via FOX Sports Betting Analyst Jason McIntyre:

In what world are the Giants scoring two touchdowns? 

The Giants are down two starting offensive linemen, and they feature RT Evan Neal who grades out at 70th among 71 tackles per Pro Football Focus. New York should be overwhelmed at the line of scrimmage. 

That’s what happened in the opener against the Cowboys, and the Giants were held to 2.6 ypp and shutout. 

Now that you remove Saquon Barkley, it gets terrifying. 

Maybe there’s a Brock Purdy mistake or two, or perhaps the Giants get some special teams luck, but if that doesn’t happen, I don’t see how the Giants score enough to cover the spread. 

With Purdy at the helm, the 49ers offense has topped 30 in seven of the last eight regular season games. And San Francisco is 7-0 straight up and against the spread in its last seven home games.

Look for the 49ers to cruise in this spot. 

PICK: 49ers (-10) to win by more than 10 points
PICK: Giants team total under 16.5

How to Watch San Francisco vs. New York

• Game Date: Thursday, September 21, 2023
• Time: 8:15 PM ET
• Venue: Levi's Stadium
• Location: Santa Clara, California
• TV: Watch on Amazon Prime Video

49ers vs. Giants Recent Matchups

• Over their last five meetings, New York has tallied three wins versus San Francisco.
• Over their last five head-to-head matchups, New York has put up 114 points, while San Francisco has accumulated 100.

San Francisco Betting Info

• San Francisco won 11 games against the spread last season, failing to cover six times.
• The 49ers did not lose ATS (1-0) as a 10.5-point favorite or more last season.
• San Francisco games went over the point total nine out of 17 times last season.
• The 49ers finished 13-3 in games they were listed as the moneyline favorite last season (winning 81.2% of those games).
• San Francisco played as a moneyline favorite of -535 or shorter in only one game last season, which it won.
• The implied moneyline probability for this matchup gives the 49ers an 84.3% chance to win.

49ers Stats (2022)

San Francisco's Key Players

Offense

• Christian McCaffrey rushed for eight touchdowns last year, and racked up 1,139 total rushing yards (67 per game and 4.7 per carry).
• McCaffrey also played a role the passing game with 741 yards (43.6 per game) on 85 receptions (five per game), while being targeted 108 times. He had five receiving touchdowns.
• Brandon Aiyuk put together a 2022 stat sheet that included 78 catches for 1,015 yards and eight receiving touchdowns over 17 games played. He was on the receiving end of 114 targets and averaged 4.6 receptions per game.
• George Kittle put up 765 receiving yards and 11 touchdowns (third in the NFL) on 60 receptions while being targeted 86 times last season.
• Deebo Samuel had 56 catches for 632 yards and two receiving touchdowns. He averaged 4.3 yards per game over 13 games and was targeted 94 times.

Defense

• Nick Bosa had 51 tackles, 19 TFL, 18.5 sacks, and one pass defended in 2022.
• Fred Warner had one interception on top of 130 tackles, three TFL, two sacks, and 10 passes defended.
• Dre Greenlaw intercepted one pass on top of127 tackles, three TFL, and six passes defended during the 2022 season.
• Talanoa Hufanga registered two sacks to go with five TFL, 95 tackles, and four interceptions in 17 games.

New York Betting Info

• New York won 13 games against the spread last year, failing to cover four times.
• The Giants covered every time (1-0) as underdogs of 10.5 points or more last year.
• In New York games last season, combined scoring went over the point total seven times.
• The Giants were underdogs 12 times last season and won six, or 50%, of those games.
• Last season, New York was at least a +400 underdog on the moneyline one time, losing that contest.
• The sportsbooks' moneyline implies a 20.0% chance of a victory for the Giants.

Giants Stats (2022)

New York's Key Players

Offense

• Daniel Jones passed for 3,205 yards last year, with 15 TDs and five interceptions. He completed 67.2% of his passes, averaging 200.3 yards per game and 6.8 per attempt.
• He added 708 yards on the ground, and scored seven rushing TDs. He averaged 44.3 yards per game and 5.9 per attempt.
• Saquon Barkley averaged 82 rushing yards in 16 games (1,312 total yards to rank fourth in the NFL), and scored 10 rushing TDs.
• Barkley also had 57 catches for 338 yards. He was targeted 76 times and averaged 21.1 yards per game.
• Last year for the Colts, Parris Campbell caught 63 passes for 623 yards with three TDs . He was targeted 91 times, and averaged 3.7 receptions in 17 games.
• Darius Slayton had 46 receptions for 724 yards and two TDs. He averaged 3.5 yards per game in 13 games and was targeted 71 times.

Defense

• During the 2022 season for the Colts, Bobby Okereke had six TFL and 149 tackles in 17 games.
• Isaiah Simmons posted 99 tackles, five TFL, four sacks, and two interceptions for the Cardinals.
• Dexter Lawrence posted 7.5 sacks in addition to his seven TFL and 68 tackles.
• Kayvon Thibodeaux registered four sacks plus six TFL and 49 tackles over 13 games.