The loss tied the second-largest ever by an AP top-10 Duke team against an unranked opponent. In the 1968 NIT, 10th-ranked Duke lost by 29 to Saint Peter's. The Blue Devils' other 22-point loss was in 1956, also against NC State.
Devon Daniels added a career-high 25 points for the Wolfpack, who led by 15 at halftime and by as much as 27 late in a surprisingly lopsided victory against the Blue Devils, who entered the game atop the ACC.
"We knew this was a big game as a team,'' Daniels said. "We really locked in on the [scouting report], really looked at their tendencies and we knew we were going to have to bring it from the very jump.''
The 22-point win was the Wolfpack's largest over a top-10 team since 1965, when they beat Saint Joseph's by 22. It ties their second-largest victory ever against an AP top-10 team.
It was a desperately needed marquee win to boost the NCAA tournament résumé for the Wolfpack, who saw their chance to make the tournament jump from 16% to 26%, according to ESPN's Basketball Power Index (BPI).
"We talked about the last couple of days what a great opportunity this would be and we stepped up to the challenge,'' NC State coach Kevin Keatts said.
With the loss, Duke went from an 82% chance to a 78% chance to secure a 1-seed, and from a 96% chance to an 86% chance to win a share of the ACC title.
Duke has now lost six of eight in PNC Arena dating to 2010, with five of those coming against the Wolfpack and one being an NCAA tournament loss to Mercer in 2014.
Vernon Carey Jr. scored 27 points to lead Duke, which shot 38% and struggled both at the line and from the arc. The Blue Devils made just 4 of 17 3-pointers and 10 of 22 free throws, part of an all-around shaky showing that included a complete inability to slow Johnson and Daniels in the first half.
Johnson and Daniels combined for 33 first-half points to single-handedly outscore the Blue Devils (29), the last coming when Johnson banked in a runner from just beyond halfcourt for a 44-29 lead at the break.
Johnson had also hit a halfcourt shot to close the first half of the Wisconsin win and hit one at the buzzer to win at UNC Greensboro.
"I shoot them every day after practice,'' Johnson said. "I'm going to keep shooting them.''
Duke got as close as 11 with about 11 minutes left, only to see Johnson answer with a 3 before DJ Funderburk followed with a three-point play to push the margin back to 67-52 with 8:31 left.
The lead only grew from there, with Wolfpack fans storming the court to celebrate when the final horn sounded.
The Blue Devils hadn't lost since dropping back-to-back games to Clemson and current No. 11 Louisville in mid-January, moving past the Cardinals and into the ACC lead as Louisville stumbled twice last week. Yet they didn't come out Wednesday with anything approaching the same edge as the Wolfpack, getting down 10-1 out of the gate and watching that margin push well past 20 after halftime.
From there, there would be no repeat of the wild comeback at North Carolina, with Duke never getting the lead to single digits after halftime.
The Blue Devils host Virginia Tech on Saturday, with eighth-ranked Florida State visiting NC State the same day.
ESPN Stats & Information and The Associated Press contributed to this report.