Skinner won the matchup of elite Atlantic Coast Conference quarterbacks by throwing for a career-high 361 yards, while the Demon Deacons (3-2, 1-1) became the first team to intercept Wilson in more than a year.
Wilson's streak was snapped at 379 attempts when Josh Bush picked off the sophomore in the second quarter. Redshirt freshman Kenny Okoro then intercepted him in the end zone with 2:02 left and the Wolfpack (3-2, 0-1) lost in their first road game of the season.
Chris Givens had eight catches for 113 yards and a TD and Wake Forest overcame six sacks to beat NC State for the fourth time in five meetings.
Skinner's nifty 25-yard strike to Givens in the back of the end zone on third-and-21 early in the fourth quarter gave Wake Forest a 27-17 lead. It was Skinner's 45th TD, passing Gary Schofield and Brian Kuklick on the school's career list.
Wake Forest kept N.C. State in it thanks to a costly mental error by senior defensive end Boo Robinson. He was called for a 15-yard personal foul penalty for pushing and shoving after Wilson's third-down pass fell incomplete. On the next play Wilson's 5-yard TD pass to Toney Baker made it 27-24.
But speedy Lovell Jackson's 80-yard kickoff return set up Jimmy Newman's 21-yard field goal with 4:44 left.
That gave Wilson another shot. Facing third-and-6, a scrambling Wilson dumped a shovel pass to Jamelle Eugene for a 21-yard gain to the Wake 39. But soon after Wilson's pass to the back of the end zone was picked off by Okoro, making his first career start at cornerback.
Struggling with his accuracy and plagued by some drops, Wilson finished 20 of 43 for 275 yards and two touchdowns and two rare turnovers.
The first interception, coming on first-and-35 after consecutive penalties, sailed into double coverage. Bush made an easy catch - waiting for the ball to come down to him - for his first career interception.
It was Wilson's second career pick and his first in 14 games, dating to the third quarter against Clemson on Sept. 19, 2008. He had broken the previous Football Bowl Subdivision record of 325 passes without an interception by Kentucky's Andre Woodson in 2006-07.
Skinner's first two touchdown passes went to Marshall Williams, who had a key drop in the end zone late in Wake Forest's loss to N.C. State last season.
Marshall's 11-yard catch midway through the third quarter put the Demon Deacons ahead 20-10.
Wilson was not finished, however. After completing only 12 of his first 28 passes, he had a 41-yard completion to Owen Spencer before his 14-yard scrambling TD run cut the deficit to 20-17 entering the fourth quarter.
Skinner set a career high in yards passing for the third straight, while completing 31 of 45 passes, overcoming two interceptions and persevering despite intense pressure.
The Demon Deacons came in having allowed only three sacks, but they were shuffling their offensive line all game because of injuries.
Willie Young had three sacks for N.C. State.