Tarvaris Jackson threw for 166 yards with a touchdown and an interception on 15-of-22 passes for Seattle (2-3), but left the game in the third quarter with a bruised right shoulder.
Charlie Whitehurst took over at quarterback and completed 11-of-19 passes for 149 yards, including the go-ahead score in the fourth quarter.
Marshawn Lynch totaled 98 yards on the ground with a touchdown on 12 carries, and Doug Baldwin hauled in eight passes for 136 yards and a TD for Seattle.
Eli Manning completed 24-of-39 passes for 420 yards and three touchdowns, but also tossed three interceptions for New York (3-2).
Victor Cruz caught eight passes for a career-high 161 yards and a score in a losing effort.