James Franklin threw for 343 yards and two touchdowns, and defensive end Kony Ealy returned an interception 49 yards for a score to lead Missouri past Indiana 45-28 on Saturday night.
The Tigers (3-0) won in Bloomington for the first time since 1953 and ended an eight-game winless streak in this series, though the teams hadn't played since 1992.
Indiana (2-2) was led by Nate Sudfeld who threw for 229 yards and one TD, but he was picked off three times.
The Hoosiers are now off until hosting Penn State on Oct. 5.
It was the only regular-season meeting between schools from the Big Ten and SEC, but the highly-anticipated shootout became a one-sided affair after the Hoosiers tied the score at 14 midway through the second quarter.
Franklin broke the tie with his 1-yard TD run.
Then 275-pound Ealy picked off Sudfeld and scored to make it 28-14.