Weatherford completed 21-of-35 passes, while Willie Reid had an 83-yard punt return for a touchdown to spark a string of 24 unanswered third-quarter points for the underdog Seminoles (8-4). Reid added 79 receiving yards on five catches and was selected the game's Most Valuable Player.
The Hokies (10-2) were held to 86 rushing yards on 31 attempts. Quarterback Marcus Vick threw for a career-best 335 yards with a score on 26-of-52 passing, but was sacked six times and picked off once.
Virginia Tech's Josh Morgan finished with 128 yards on seven grabs, including a 28-yard touchdown in the Hokies' fourth-quarter rally.
Virginia Tech entered the game ranked first in the country in scoring defense, total defense and pass defense.
Dennis Rodman pledges to end trips to North Korea
Interpol investigating stolen passports on missing flight