Week 3 of the 2023 NFL schedule gets underway when the San Francisco 49ers play their home opener against the New York Giants on Thursday Night Football. The 49ers (2-0) began the campaign with road victories against Pittsburgh and the NFC West-rival Los Angeles Rams to extend their regular-season winning streak to 12 games. New York (1-1) visits San Francisco for the first time since 2018 after staging a 21-point comeback, the team's largest of the Super Bowl era, in a 31-28 triumph at Arizona in Week 2. The Giants will be without star running back Saquon Barkley, who suffered an ankle injury last week. The 49ers will be without wide receiver Brandin Aiyuk (shoulder).

Kickoff from Levi's Stadium is set for 8:15 p.m. ET. San Francisco is a 10.5-point favorite in the latest Giants vs. 49ers odds, while the over/under for total points scored is 44. Before making any 49ers vs. Giants picks, you need to see the NFL predictions and betting advice from SportsLine's Advanced Computer Model.

The model, which simulates every NFL game 10,000 times, is up more than $7,000 for $100 players on top-rated NFL picks since its inception. The model enters Week 3 of the 2023 NFL season on an incredible 164-117 run on top-rated NFL picks that dates back to the 2017 season. It is also on an 18-9 roll on top-rated NFL picks since Week 7 of last season.

The model also ranked in the top 10 on NFLPickWatch four of the past six years on straight-up NFL picks and beat more than 94% of CBS Sports Football Pick'em players four times during that span. Anyone who has followed it is way up.

Now, the model has set its sights on 49ers vs. Giants and just locked in its picks and Thursday Night Football predictions. You can head to SportsLine now to see the model's picks. Here are several NFL odds and betting lines for Giants vs. 49ers: 

  • Giants vs. 49ers spread: San Francisco -10.5
  • Giants vs. 49ers over/under: 44 points 
  • Giants vs. 49ers money line: San Francisco -547, New York +401
  • SF: 49ers are 14-8 against the spread, including playoffs, since the start of the 2022 season 
  • NYG: Giants are 0-2 ATS this year after going 14-5 in 2022, including playoffs
  • Giants vs. 49ers picks: See picks at SportsLine

Why the 49ers can cover

The Giants are 26th in the NFL against the run, allowing an average of 136.5 yards on the ground. They'll have their hands full with Christian McCaffrey, who leads the league with 268 rushing yards after becoming the first 49er since Garrison Hearst in 1998 to open a season with back-to-back 100-yard performances. The 27-year-old McCaffrey has been finding the end zone with regularity as he has recorded a scrimmage touchdown in 11 consecutive contests.

With a TD against New York, McCaffrey will match the longest streak in franchise history set in 1987 by Jerry Rice. It also would be the longest run in the NFL since Arian Foster scored in 13 straight contests from 2011-12. McCaffrey, who has 22 career touchdown receptions, posted his 40th scoring run in last week's 30-23 victory against the Rams to join Chuck Foreman, Neal Anderson, Marshall Faulk and Alvin Kamara as the only players in the Super Bowl era with at least 40 rushing touchdowns and 20 TD catches in their first seven NFL seasons. See which team to pick here.

Why the Giants can cover

After throwing for only 166 yards with no touchdowns and three interceptions over the first six quarters of the season, Daniel Jones became a different quarterback in the second half against Arizona. The 26-year-old completed 17-of-21 pass attempts for 259 yards and a pair of TDs as New York matched the largest comeback in franchise history. Jones also gained 58 of his 59 rushing yards and ran for a score after halftime as he joined Michael Vick (2010) as the only NFL players since 2000 with at least 250 passing yards, 50 rushing yards, two touchdown passes and a scoring run in one half.

The comeback helped give added confidence to the Giants, who were 7-1 against the spread as road underdogs last season - Brian Daboll's first as head coach. Another good sign for the team was the play of rookie wide receiver Jalin Hyatt last week. Selected from the University of Tennessee in the third round of the 2023 NFL Draft, the 21-year-old made his first two career catches, with both coming during New York's second-half rally and being for more than 30 yards. See which team to pick here.

How to make 49ers vs. Giants picks on TNF

SportsLine's model is leaning Over the point total, calling for 45 combined points. The model also says one side of the spread cashes in nearly 60% of simulations. You can only see the model's TNF picks at SportsLine.

So who wins 49ers vs. Giants on Thursday Night Football, and which side of the spread cashes almost 60% of the time? Visit SportsLine now to see which side of the 49ers vs. Giants spread you need to jump on, all from the model on a 164-117 roll on NFL picks, and find out.