The old-time college football game that's considered the biggest upset in the early days of college football was in 1921, when Centre College of Kentucky downed Harvard 6-0. That game was voted the greatest football upset of the half-century by the AP in 1950. Harvard hadn't lost since 1918, and Centre was the smallest college they had ever played.
After the 1919 season, Harvard won the Rose Bowl and was considered to be the National Champion. In 1920, they went undefeated, with a tie against then-powerhouse Princeton, who was considered NC that year.
Although Harvard had been tied by Penn State the week before the Centre game, nobody game the little college from Kentucky a chance when they went to Massachusetts.
Last year, ESPN named it the biggest upset in college football history.
Centre College: A U.S. News Top 50 Liberal Arts College