Giants vs. 49ers prediction, odds, spread, injuries, trends for NFL Week 3

Should bettors trust the 49ers to cover the spread in Week 3?
San Francisco 49ers running back Christian McCaffrey (23).
San Francisco 49ers running back Christian McCaffrey (23). / Gary A. Vasquez-USA TODAY Sports

The 2-0 San Francisco 49ers have the best odds to win the Super Bowl in the NFL right now, and they’re heavily favored on Thursday Night Football against the New York Giants in Week 3. 

The Giants are off a comeback win against the Arizona Cardinals in Week 2, but they have looked bad for six of the eight quarters they’ve played so far this season. 

To make matters worse for New York, star running back Saquon Barkley was injured in Week 2. Originally, it was reported that his ankle injury would keep him out for three games, but now Giants head coach Brian Daboll is saying Barkley has a chance to play against San Fran. 

Even if Barkley does suit up, the Giants are facing an uphill battle against one of the best rosters in the NFL. The 49ers have a plethora of playmakers on both sides of the ball, and quarterback Brock Purdy has yet to lose a game in the NFL during the regular season. 

Can the 49ers cover the spread in this matchup? 

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Giants vs. 49ers odds, spread and total for Week 3

Giants vs. 49ers betting trends

  • The 49ers are 1-1 against the spread this season.
  • The Giants are 0-2 against the spread this season. 
  • The OVER is 1-1 in the Giants and 49ers games this season.
  • The Giants are 14-7 ATS under head coach Brian Daboll.
  • The 49ers are 17-16-1 ATS as home favorites under Kyle Shanahan. 

Giants vs. 49ers injury reports 

New York Giants injury report

  • Saquon Barkley (ankle) – game-time decision
  • Wan’Dale Robinson – questionable
  • Andrew Thomas – questionable
  • Azeez Ojulari – questionable
  • Ben Bredeson – questionable
  • Micah McFadden – questionable

San Francisco 49ers injury report

  • Ambry Thomas – questionable
  • Brandon Aiyuk (shoulder) – questionable

Giants vs. 49ers how to watch

  • Date: Thursday, Sept. 21
  • Game Time: 8:15 p.m.
  • Venue: Levi's Stadium
  • How to Watch (TV): Amazon Prime
  • Giants Record: 1-1
  • 49ers Record: 2-0

Giants vs. 49ers key players to watch

New York Giants

The running back room: With Barkley looking like a game-time decision at best with an ankle injury, the Giants could be turning to either Matt Breida, Eric Gray or Gary Brightwell in the backfield this week. Breida – a former 49er – is a speedy back, but he may not be able to handle a full workload this week. New York needs to have some semblance of a running game to have any chance at an upset. 

Darren Waller: Is the Darren Waller breakout coming? After making just three catches in Week 1, Waller came alive for six catches and 76 receiving yards in Week 2. Daniel Jones looked much better against Arizona, and he could carry that into Thursday’s game. 

San Francisco 49ers

Brock Purdy: When wouldn’t Purdy be a key player to watch? The former Mr. Irrelevant continues to win in San Francisco, and he’s played turnover-free football through the first two weeks. He didn’t throw a touchdown in Week 2, but he did get in the end zone on the ground. If he keeps playing this well, San Fran is going to be tough to beat. 

Christian McCaffrey: The NFL’s best running back is showing why he’s so dynamic, rushing for over 100 yards in each of the first two weeks of the season. The Giants have been run on a bit in the first two weeks of the season, so they could be in trouble if CMC gets going again on Thursday. 

Giants vs. 49ers prediction and pick

I’m going to lay the 10 points with the 49ers in this game and expect a blowout. 


Well, first off the Giants looked terrible when they played elevated competition in Dallas – at home even – in Week 1. The team lost that game 40-0 and couldn’t stop the Cowboys’ pass rush. Are they going to fare any better against Nick Bosa and company? 

With Barkley potentially out, the Giants are going to be relying heavily on Daniel Jones, who didn’t come alive until the second half last week against the worst team in the NFL. 

San Francisco is arguably the best team in the league, averaging 6.3 yards per play this season on offense (No. 2 in the league) while allowing just 4.5 yards per play on defense (No. 5 in the NFL). 

The team has run for well over 100 yards in each of its first two games, and the Giants showed in Week 2 that they struggle to stop the run, allowing James Conner to clear the century mark on 23 carries. 

San Fran was up 10 on the Los Angeles Rams in Week 2 before a meaningless (in the sense of the final score) last second field goal – very meaningful if you bet on the spread which was Rams +7.5 – cut the lead to seven. 

Prior to that, the 49ers won by 23 and stifled the Pittsburgh offense in Week 1. Both of those wins came on the road, and I expect the 49ers to be even better in Santa Clara. 

Game odds refresh periodically and are subject to change.

Find Peter Dewey's betting record here.