The Big Six Conference, a former NCAA-affiliated major college athletic association that sponsored American football, was formed in 1928 when six members of the Missouri Valley Intercollegiate Athletic Association departed that conference to establish the Big Six. Charter members included Iowa State, Kansas, Kansas State, Missouri, Nebraska, and Oklahoma.

The Big Six Conference remained intact until 1948, when the six charter members were joined by Colorado to create the Big Seven Conference.

The six charter members of the former Big Six Conference have been affiliated with the Big Twelve Conference since 1996.