1 p.m. ET | FOX
Matchup rating: 44.3 | Spread: SF -4 (41)
What to watch for: Who is playing -- and where -- for each team? The 49ers are without their top two running backs, quarterback Jimmy Garoppolo, Defensive Rookie of the Year Nick Bosa and several others. The Giants are missing Saquon Barkley and Sterling Shepard. Who takes their spots? And can they be capable fill-ins? Start with 49ers backup quarterback Nick Mullens and newly-signed Giants running back Devonta Freeman. All eyes will be on those two. -- Jordan Raanan
Bold prediction: 49ers running back Jerick McKinnon will have his first 100-plus-yard rushing game since 2014 and just the third in his career. With Raheem Mostert and Tevin Coleman out because of knee sprains, McKinnon will have an expanded role this week, and he gets it against a Giants defense that has been shoddy against the run over the first two weeks and hasn't seen a rushing attack as dangerous as the Niners' unit yet. McKinnon will take advantage and reach the end zone for the third time in as many weeks. -- Nick Wagoner
Stat to know: Giants quarterback Daniel Jones has nine games with at least two turnovers since 2019, tied with Jameis Winston for the most in the NFL in that span -- and that includes three straight dating back to last season.
What to know for fantasy: It's been over 1,000 days since McKinnon (roughly 80% available) has had 15 carries in a game, but with Mostert and Coleman out, the path to volume has been paved. See Week 3 rankings.
Betting nugget: Since 2017, the Giants are 2-14 ATS as a home underdog of less than seven points. Read more.
Wagoner's pick: 49ers 20, Giants 17
Raanan's pick: 49ers 22, Giants 20
FPI prediction: SF, 67.3% (by an average of 6.3 points)
Matchup must-reads: 49ers seek peace of mind before returning to turf of terror ... Giants sign Pro Bowl running back Freeman ... An MCL injury, a baby on the way and matching Jim Brown: Mostert's wild week ... Manning content with retirement and helping Giants QB Jones out