New York also ended a three-game losing streak against the Saints, who turned over the ball four times in losing their third straight.
Manning had TD passes of 6 yards to Martellus Bennett, 5 yards to Domenik Hixon, 25 yards to Hakeem Nicks and 10 yards to Victor Cruz. Wilson scored on runs of 6 and 52 yards and finished with 100 yards on 13 carries for the biggest day of his short career.
The 52 points were their most since scoring 55 against Green Bay in 1986. It also was the most given up by New Orleans, whose defense is run by former New York coordinator Steve Spagnuolo.
Darren Sproles scored on a 13-yard run and caught a 9-yard touchdown pass from Brees late in the third quarter, cutting the Giants lead to 35-27.
However, Jerrel Jernigan returned the ensuing kickoff 60 yards to set up Manning's touchdown pass to Cruz. New York iced the game when Stevie Brown returned one of two interceptions thrown by Brees to set up Lawrence Tynes' 39-yard field goal.
The biggest play was Wilson's kickoff return, which came one play after Elbert Mack intercepted Manning in the left flat and returned it 73 yards to give the Saints a 7-0 lead. l
The touchdown came minutes after Dallas rallied for a 20-19 win over Cincinnati and Washington beat Baltimore 31-28 in overtime despite losing Robert Griffin III to a knee injury.
The Giants could have folded against a team that had routed them the past two meetings. Instead, Wilson, who has been threatening all season to break a kickoff, fielded one at the 3, went up the middle and then veered toward the right corner of the end zone. He capped it with a somersault.
A fumble near midfield Jed Collins led to Manning's touchdown pass to Bennett and New York never trailed again.
Manning finished 22 of 35 for 259 yards and two interceptions. Brees, who had never lost to the Giants and had eight TD passes and no interceptions in the last two games, finished 26 of 43 for 354 yards. New Orleans outgained New York 487-394, but mistakes were its undoing.
The Giants didn't cash in after Wilson's returns of 58 and 52 yards, but his 20-yarder late in the half after a short kickoff set up a 69-yard touchdown drive. Manning capped it with the fade route to Hixon.
Defensive tackle Linval Joseph returned Collins' miscue 16 yards to the Saints 35. A 16-yard pass to Hixon and a couple of penalties set up a 6-yard touchdown toss to Bennett for a 14-7 lead.
Brees took the Saints on drives of 81 and 67 yards in the second quarter, but each time the NFL's top red-zone offense settled for field goals of 32 and 25 yards by Garrett Hartley.
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New Orleans 27, N.Y. Giants 52
New Orleans 7 6 14 0 27
N.Y. Giants 14 7 14 17 52
NO • Mack 73 interception return (Hartley kick), 9:38.
NYG • Wilson 97 kickoff return (Tynes kick), 9:25.
NYG • Bennett 6 pass from Manning (Tynes kick), 4:19.
NO • FG Hartley 32, 9:46.
NO • FG Hartley 25, 1:57.
NYG • Hixon 5 pass from Manning (Tynes kick), :20.
NYG • Wilson 6 run (Tynes kick), 13:04.
NYG • Nicks 25 pass from Manning (Tynes kick), 8:13.
NO • Sproles 13 run (Hartley kick), 7:21.
NO • Sproles 9 pass from Brees (Hartley kick), 1:51.
NYG • Cruz 10 pass from Manning (Tynes kick), 14:20.
NYG • FG Tynes 39, 10:19.
NYG • Wilson 52 run (Tynes kick), 5:10.
Attendance • 81,437.
First downs 22 24
Total Net Yards 487 394
Rushes-yards 24-142 27-135
Passing 345 259
Punt Returns 2-5 2-19
Kickoff Returns 8-149 6-287
Interceptions Ret. 2-85 2-91
Comp-Att-Int 26-43-2 22-35-2
Sacked-Yards Lost 1-9 0-0
Punts 4-50.5 3-38.7
Fumbles-Lost 2-2 0-0
Penalties-yards 10-81 6-55
Time of Possession 30:18 29:42
Rushing • New Orleans, Ingram 13-68, Sproles 5-56, P.Thomas 5-19, Brees 1-(minus 1). N.Y. Giants, Wilson 13-100, Bradshaw 11-33, Hynoski 1-5, Manning 2-(minus 3).
Passing • New Orleans, Brees 26-43-2-354. N.Y. Giants, Manning 22-35-2-259.
Receiving • New Orleans, P.Thomas 7-57, Graham 5-56, Colston 4-61, Sproles 4-28, Morgan 2-106, Collins 2-9, Moore 1-26, Henderson 1-11. N.Y. Giants, Cruz 8-121, Bennett 5-32, Nicks 4-67, Hixon 3-30, Hynoski 2-9.
Missed Field Goals • N.Y. Giants, Tynes 36 (WL).