Saint Joseph High School opened its doors at its original location at 1441 North Michigan Street in September of 1953 under the name of Saint Joseph's High School. The new Catholic high school was the result of the merger of three schools: South Bend Central Catholic, Saint Joseph's Academy, and South Bend Catholic which had absorbed Saint Hedwig's High School. The first graduating class was presented their diplomas in the spring of 1954. Originally, male and female students attended separate classes, with the building divided into halls by gender. Classes were integrated in the late 1960's. 
After serving the community for fifty-nine years, the original building was vacated in the summer of 2012 and sold to the University of Notre Dame. The Forward in Faith campaign raised funds for a new school building at 453 N. Notre Dame Avenue, the former site of the Saint Joseph Regional Medical Center. Coinciding with the move was a change in the name of the school to Saint Joseph High School. The new building was dedicated in August of 2012.
The 2013-2014 school year marked the sixtieth anniversary of Saint Joseph High School as a Catholic secondary school dedicated to transforming students in heart and mind, preparing them to serve God, the Church, and the world.