Since the FCS and Division II have both been mentioned, it's only fair to mention Division III. And even if it wasn't only fair, this game would still make the list.
In the 2003 season opener, the Trinity Bible College Lions traveled to Rockford, Illinois to take on the Rockford College Regents.
Almost from the opening kickoff, it was clear that Trinity Bible College was in for a very, very long night. After an opening drive punt by Trinity Bible, the Regents took just five plays to score their first of many, many touchdowns on the evening. A three-and-out by Trinity Bible led to another Rockford touchdown. Then a safety. Then another touchdown. Then another. And another.
When the afternoon was over, the 918 people in attendance could hardly believe the scoreboard—which had been rendered useless. The final score was Rockford 105, Trinity Bible 0.
Rockford broke the 25-year-old Division III scoring record with their 105 points, breaking Concordia-Moorhead's 97 points in 1977. Rockford gained 548 yards of offense, and held Trinity Bible to just 14. No, that's not a misprint. Fourteen yards. With 61 total plays, the Lions were only able to manage just 14 yards of total offense, including -34 yards rushing. Trinity Bible also committed six turnovers during the game.
Of Trinity Bible's 18 drives, 12 ended with zero of negative yards. The Lions' third drive starter on their own 18, but ended with a safety. They had the ball just once in Rockford territory, but lost the ball on a failed fourth-down conversion. Trinity Bible was just 1-for-18 on third downs.
All in all, it was a complete and utter failure for Trinity.
It also stands as the most points scored and largest margin of victory for any college football team across all NCAA divisions over the last decade.