Junior quarterback Blake LaRussa entered the game in ODU’s second offensive series and threw for 495-yards, four touchdowns and rushed for one.
The win is ODU’s first over a power-five opponent since restarting football in 2009.
After Virginia Tech tied the score at 35, the Monarchs retook the lead on a 29-yard touchdown pass from LaRussa to Jonathan Duhart to give ODU a 42-35 lead with five minutes remaining.
The Hokies drove to the ODU 21 but a fourth down pass from Willis fell incomplete. The Monarchs iced the game with a 40-yard touchdown run from Jeremy Cox for a 49-35 final.
Chamarri Conner got the scoring started for Tech with an 87-yard touchdown run one play after an ODU punt to put the Hokies up 7-0.
ODU tied the score on its following drive, going 75-yards in six plays capped by a 14-yard touchdown pass from LaRussa to Duhart. The big play on the drive was a 20-yard scramble by LaRussa and a 37-yard completion from LaRussa to Hasaan Patterson.
The Hokies took the lead with a Josh Jackson to Sean Savoy touchdown 28-yard touchdown pass midway through the second quarter.
The Monarchs made it a 14-14 game at halftime with a four-yard score from LaRussa to Duhart.
Steven Peoples helped Tech to a 21-14 lead with a one-yard score early in the third quarter, but the Monarchs came right back with a 65-yard drive capped by a one-yard run from LaRussa to tie the score at 21.
Damon Hazleton took Tech’s first play of their following drive for a 72-yard touchdown catch, but once again ODU hung around with a 25-yard strike from LaRussa to Fulgham to once again knot the score at 28.
ODU forced Virginia Tech into a three and out, ODU took its first lead of the night on a 15-yard run from Cox. LaRussa to Duhart for 27-yards set up the touchdown run.ODU’s win marks the first time a Conference USA team has knocked off a ranked opponent since Houston defeated No. 22 Penn State in 2012.