The program began in 1901. The school then called itself St. Xavier College; the team the Saints. In their first season they played a mix of colleges and high schools, but gradually improved their schedule. In 1907 they began a rivalry against the University of Dayton, then named St. Mary's Institute.
The team name became the Musketeers in 1929, the same year St. Xavier became Xavier University and built Corcoran Stadium. The high point came under coach Edward Kluska, who posted a 35-12-2 record between 1947 and 1951. The 1949 team went 10-1 and received an invitation to the 1950 Salad Bowl, in which they defeated Arizona State University 33-21. Seven players from the 1950 and 1951 teams would later play in the National Football League. Xavier declined an invitation to the 1952 Salad Bowl.
Xavier's Board of Trustees ended the football program in 1973 following a determination that it lost $200,000 every year.