The Giants took a 7-0 lead, just like a week ago, driving 75 yards in five plays and scoring a touchdown on a 27-yard run by Saquon Barkley.
Buffalo responded by scoring touchdown on its next three possessions with drives of 75, 70 and 98 yards. A week ago, Dallas scored five straight touchdowns after the Giants had taken an early lead.
The Giants pulled within seven, 21-14, on a 4-yard touchdown pass from Eli Manning to T.J. Jones with 11:56 to play.
A 1-yard touchdown run by Frank Gore with 5:53 to play, preceded by a fourth down unnecessary roughness penalty that gave the Bills a first-and-goal at the 1-yard line, made it 28-14 and salted the game away for the 2-0 Bills.
At that point, most of the Giants fans at MetLife Stadium headed for the exits.
Defensively, the Giants have now given up nine touchdowns in two games. All have come on drives of 70 yards or more.
Manning finished 26-of-45 for 250 yards with a touchdown and a pair of interceptions. Barkley ran 18 times for 107 yards.
Wide receiver Cody Latimer was ruled out with a concussion after taking what looked like a helmet-to-helmet hit while making a catch in the fourth quarter.
The Giants hit the road to face the Tampa Bay Buccaneers in a 4:05 p.m. ET start.