It was founded in 1923 by the fourth bishop of Columbus, James J. Hartley, as a Roman Catholic college and high school seminary.

The previous motto, Euntes Ergo Docete Omnes Gentes, was a quote from the Gospel of Matthew (28:19) in the Latin Vulgate: "Going out, therefore, teach all nations."

On November 4, 1923, Bishop Hartley purchased the original 20-acre site, with ground being broken for the main building in July 1924.

The addition houses the 15,000-square-foot (1,400 m2) Robert C. Walter Student Commons Area, which serves as a new cafeteria and provides ample seating space for school and community functions.

Bob Walter and his '63 classmate, architect Robert Corna of Cleveland, initiated the concept for the Commons nearly two years ago.

On the columns supporting the roof are glass panes, which bear the names of all of the alumni of the school, written with laser.

The ground floor anchors the north end of the atrium, and houses a new kitchen, sponsored by Donatos Pizza, and restrooms.

The second and third floor connect to the original building at its rear stairwell, and to the Robert C. Walter Student Commons Area by a staircase.

On November 4, 2021, the school broke ground for its 11.5 million dollar Convocation Center named after its alumni Frank E. Murphy (who graduated in 1954).

The Brotherhood Center will repurpose the school's former gymnasium into a multifaceted area with classrooms, offices, a library, and a new space that will help students with their academics.

The centerpiece of this project is the newly purchased property which formerly housed the Dealers Lumber Company and came up for sale in the summer of 2010.

The Robert D. Walter West Campus includes the Savko Athletic Complex, comprising a six-lane running track, the artificial-turf Dominic and Kathleen Cavello Field and parking; a 13,000-square-foot training and fitness facility (weight room and 30 yard turf field for speed and agility); and the Horvath Parking Lot.

A pedestrian bridge that spans Alum Creek helps connect it with the main campus at 2010 E. Broad St.

Since St. Charles is an all-male school, the theatre department has had to use different methods to incorporate the female roles of plays and musicals.

Both prep school and seminary students performed the first plays at St. Charles in 1929 under the direction of Monsignor Joseph A. Cousins.

On August 6, 2024, the Roman Catholic Diocese of Columbus announced that the administrative model of St. Charles would change.