Kyle Singler scored a game high 19 points to go along with eight rebounds and seven assists as the Blue Devils moved to 12-1 on the season and 1-0 in the ACC.
Gerald Henderson added 15 points joining Nolan Smith (13), and Jon Scheyer in double figures for Duke which shot 41% from the floor and an impressive 19-of-20 from the free throw line.
Malcolm Delaney scored 12 points to lead Virginia Tech (9-5, 0-1). Leading scorer A.D. Vassallo was held to seven points -- 12 below his average -- and didn't score on 0-of-2 shooting in the second half.
Just moments after learning that top rated North Carolina had fallen to an unranked league opponent on its home floor, the Blue Devils looked to avoid a similar fate with a strong start - taking a 9-0 lead at the 17:08 mark when Singler knocked down a three pointer. From there the Hokies would play Duke even up until intermission, trailing 39-31.
After two Hokie layups in three possessions cut the advantage to four, head coach Mike Krzyzewski called a timeout that could be described as "colorful" as the Duke head man implored his team to pick up the defensive effort. The message was received as the Hokies would score just nine points over the remaining 17:35 of the game.
The Hokies shot 36.7 percent and committed 18 turnovers. They were denied their second straight victory at Cameron Indoor Stadium and their first win against a nationally ranked team since their overtime victory two years ago at then-No. 4 North Carolina.
Duke returns to out of conference action on Wednesday night against Davidson in Cameron Indoor.