Logan Kilgore passed for 246 yards (on 17 of 23 passes) for Middle Tennessee (3-1), of the Sun Belt Conference, as the Blue Raiders dominated the Yellow Jackets at home.
The loss was Georgia Tech's first loss to a non-BCS school since 1996. The Yellow Jackets have also lost consecutive home games for the first time since 1988.
Georgia Tech quarterback Tevin Washington tied a school record with four rushing touchdowns, but the Yellow Jackets (2-3) continued to struggle on defense.
A week earlier, Georgia Tech surrendered 609 yards of total offense, including 436 passing, as Miami came from behind for a 42-36 overtime win in their Atlantic Coast Conference game. Saturday, the Blue Raiders had 510 yards of total offense.
Georgia Tech linebacker Jabari Hunt-Days intercepted Kilgore's first pass, and Washington scored his first touchdown five plays later to give the Yellow Jackets a 7-0 lead.
Kilgore completed his next six passes, however, on Middle Tennessee's ensuing possession and the Blue Raiders tied the game when wide receiver Anthony Amos made a leaping, one-handed reception for a 4-yard touchdown.
The Yellow Jackets had gone back-to-back games without a turnover, but they lost three fumbles and Washington threw an interception on Saturday.
Georgia Tech's defense, meanwhile, picked up where it left off a week earlier and that wasn't a good thing for the Yellow Jackets even though defensive coordinator Al Groh this week worked from the coaches' box rather than the sideline for the first time in years.
Middle Tennessee twice led by a touchdown in the first half. The first came when Cunningham went 60 yards untouched up the middle on the first play of the second quarter for a 14-7 edge. The second was when he scored from 1 yard out with 4:49 left in the half for a 21-14 Blue Raiders lead.
Middle Tennessee also had a touchdown called back in the first half when a 33-yard Cunningham run was nullified by a holding penalty.
Washington's scoring runs of 3 and 1 yard in the second quarter tied the score, and the game was tied at 21 at halftime.
Georgia Tech was troubled by linebacker play as outsider starter Jeremiah Attaochu was out with an injury, and outside starter Brandon Watts did not start and played sparingly for disciplinary reasons.
Cunningham's third touchdown, a 23-yard run, and a 75-yard pass from Kilgore to wide receiver Marcus Henry -- who was covered loosely by stand-in linebacker Malcolm Munroe -- gave the Blue Raiders a 35-21 lead in the third quarter.
Washington added his fourth TD run in the fourth quarter, but that was soon followed by Georgia Tech's fourth turnover. An interception by Middle Tennessee cornerback Kenneth Gilstrap that first bounced off Yellow Jackets wide receiver Jeff Greene, and Gilstrap's 38-yard return gave the Blue Raiders the ball at Georgia Tech's 17-yard line.
Cunningham added fourth quarter scoring runs of 4 and 3 yards.
For the second week in a row, a fan fell from the bleachers during a Georgia Tech game.
Wayne Hogan, an associate director of athletics at the school, reported that a Georgia Tech student, whose name was not immediately released, fell 15 feet in the northwest corner of the stadium, where emergency medical technicians are usually stationed.
According to Hogan, the student was alert and responsive while being checked on by EMT's and was transported to Grady Hospital.