Giants vs 49ers Odds, Picks, and TNF Predictions: Injuries Loom Large For G-Men

The New York Giants are in a tough spot with this short-week matchup in Week 3. Without star Saquon Barkley, among others, can the G-Men muster any attack vs. one of the league's top defenses? Our NFL betting picks don't expect much.

Last Updated: Sep 21, 2023 6:28 PM ET Read Time: 4 min

The New York Giants fought tooth and nail for a win in Arizona last week, but it raised a lot of red flags as the defense remains a big issue.

Now, with a multi-week injury to Saquon Barkley, this offense is also in a tough spot as a double-digits NFL odds underdog vs. the best defense in the NFC — the San Francisco 49ers — in tonight's action.  

With Barkley out, injuries to the O-line, and a short week to prepare for a matchup vs. an elite defense, it's very probable this New York team stays way Under its team total of 16.5 points.

Here are my free NFL picks, along with a breakdown of the Thursday Night Football odds, for this Week 3 clash between the Giants and 49ers.

For more TNF analysis, also check out our best Giants vs. 49ers prop picks and Christian McCaffrey odds and props spotlight.

Giants vs 49ers odds

Giants vs 49ers predictions

Saquon Barkley has accounted for 86% of the team’s RB rushing yards and has a 17% target share. In all, he’s totaled 23% of the New York Giants’ total yards through two weeks and will now miss multiple games with an ankle injury, meaning the G-men will likely turn to Matt Breida to face the best defense in the NFC. With no Barkley and a lack of talent at receiver, hitting the 17-point mark is going to be difficult on the short week vs. the San Francisco 49ers.  

The 49ers showed some weaknesses in the first half vs. the Rams last week as Matthew Stafford was alleviating the pressure on his O-line with some quick passing, but DC Steve Wilks made considerable adjustments at the half and held the Rams to two field goals while generating three turnovers in the 30-23 win.

Daniel Jones has struggled as a passer this season, ranking in the bottom third in EPA/play and CPOE. If he has no run game to lean on and less time to prepare with the short week, Wilks and the Niners defense will dominate at home on Thursday night, especially vs. this injury-riddled offensive line.

The Giants lost starting left guard Ben Bredson to a concussion in Week 2 while left tackle Andrew Thomas was inactive with a hamstring injury. Thomas is the team’s best pass blocker and if the left-side duo can’t get right on the short week, this 49ers pass rush that ranks Top 3 in pressure percentage and hurry rate could get to Jones with ease. 

The Niners currently rank third in EPA/play on defense and have been elite against the pass, holding opposing QBs to a 68 passer rating, which ranks fourth in the league. They give up yards, but not big plays. Considering they’re facing an offense starting Breida, Darius Slayton, Isaiah Hodgins, and Parris Campbell, racking up first downs vs. the Niners in a second consecutive West Coast matchup is going to be hard.  

This New York offense could also be out of rhythm all night as the defense has been atrocious. This squad was outscored 60-0 over its first six quarters of the season and is a Bottom-5 unit heading into prime time. The 49ers defense should be at full strength as corner Deommodore Lenoir was evaluated for a head injury on Sunday but was allowed to return while depth corner Ambry Thomas hurt his knee but also returned.

With a short week, a bad defense, no Barkley, a tough matchup, and injuries to the O-line, I don’t give this New York offense a fighting chance to produce and neither do oddsmakers who have moved this line to -11 in some places.

My best bet: Giants team total Under 16.5 (-106 at FanDuel)
Picks made at time of writing may not reflect live odds.

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Giants vs 49ers same-game parlay


Giants team total Under 16.5

Isaiah Hodgins Under 30.5 receiving yards

Dallen Waller Over 4.5 receptions

The Giants' offense is in a bad place on a short week and has not scored first in 16 of its last 19 games. That will continue on Thursday. New York has played from behind too much over the last two seasons and this is not a fun defense to chase points against.

Isaiah Hodgins could see few reps with the emergence of Jalin Hyatt and his 36.4% target share on routes run is unsustainable.

Darren Waller leads the team with a 20% target share and should see plenty of targets underneath against a defense that forces shorter throws.

Learn how to bet a same-game parlay with these helpful tips and strategies.

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Giants vs 49ers spread and Over/Under analysis

The 49ers were -9.5 on the look-ahead, reopened at -10.5, and hit as high as -11 in some spots. The Barkley injury pushed this across the 10, but the state of the Giants as a whole likely impacted the number, too. 

Healthwise, the 49ers are solid on defense but might be without Brandon Aiyuk, who played through a shoulder injury Sunday and could miss the Thursday nighter. He has 41% of the team’s air yards on a 25% target share but there are still a lot of weapons San Francisco can lean on Thursday if Aiyuk sits including Deebo Samuel, George Kittle, and Jauan Jennings. Aiyuk's absence won't mean as much to San Francisco as Barkley’s will to New York.

The G-Men are also dealing with injuries to the O-line as their left tackle missed Week 2 and their starting LG exited Sunday’s game. The 49ers D-line could have a huge advantage vs. a team where 33% of the offensive yards have come from the legs of Barkley and Jones. 

Looking at the total, it was 43.5 on the look-ahead and has hit as high as 45 as of Tuesday. 

The Niners gave up over 300 yards passing last week but also didn’t allow a completion of more than 20 yards. In Week 1, Kenny Pickett was in trail mode early and still only had 232 yards passing on 46 pass attempts vs. the Niners. San Fransisco’s 4.9 yards per pass attempt on defense ranks sixth in football. Big chunks of yards will not be there for the Giants on Thursday. 

The 49ers will absolutely be doing the heavy lifting for this total and bettors looking to hit their team total Over will have to do so on a hefty 27.5-point total with some tax. 

San Francisco has a Top-3 offense in EPA/play but the Aiyuk injury is a little worrisome as he has been Brock Purdy’s main man through two weeks. Purdy also missed some layup throws last week vs. the Rams. Next Gen Stats has Purdy at a -0.1% CPOE, just below Sam Howell and the aforementioned Jones. 

It’s tough to predict how dominant this 49ers offense will be because the matchup is great but how aggressive will it be with a big lead? It did run 66 plays for nearly 400 yards vs. a very good Pittsburgh defense in Week 1 and with the defense likely giving it some short fields, a third straight 30-point performance is more likely than doubtful, even without Aiyuk.

It should be noted that the 49ers are the slowest pace-of-play team at 34.53 seconds per play while the Giants also rank in the bottom half of the league.

Looking at player usage for prop purposes, New York receiver Jalin Hyatt has 40% of the team’s receiving yards when he is on the field. He saw just 14 snaps in Week 2 but had two grabs for 80-plus yards and a score. The rookie should move up the depth chart this week. 

Breida will be the starting back with Barkley out. Gary Brightwell is listed as the No.3 RB on the team’s depth chart.

Samuel leads the team with a 30% target share while Kittle (17%) and Christian McCaffrey (15%) trail. Jennings has just two grabs but also leads the team with a 20-yard aDOT. If Aiyuk sits, that’s a 27% target share and 41% air-yard share that will go somewhere else.  

Giants vs 49ers betting trend to know

The New York Giants have scored first in 3 of their last 19 games (-14.45 Units / -66% ROI). Find more NFL betting trends for Giants vs. 49ers.

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Giants vs 49ers game info

Location: Levi Stadium, San Francisco, CA
Date: Thursday, September 21, 2023
Kickoff: 8:20 p.m. ET
TV: Amazon Prime or NBC
Opening odds: 49ers -9.5, 43.5

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