The school was founded in the Archdiocese of Indianapolis by Bishop Joseph Chartrand in 1918 and was run by the Brothers of Holy Cross until it became independent by the late 1970s.

In the 1970s, with the departure of the Brothers, a non-profit trust was developed by Robert V. Welch, other parents, and a lay board in an effort to keep Cathedral alive.

As part of that change, the school moved from its longtime home in downtown Indianapolis to its present location at 56th and Emerson streets, the site of the former all-girls Ladywood St. Agnes Academy.

Cathedral was the only high school, public or private, in the state of Indiana to receive a Blue Ribbon designation in 2016.

The Language Support Program is designed specifically to meet the needs of dyslexic students preparing for college entrance.

[6][citation needed] As of the end of the 2013 IHSAA football season, Cathedral had more wins than any other school in the history of the sport in the state of Indiana.

[7] As of 2021 Cathedral ranks first on the all-time list for State Finals appearances in Indiana, having reached the title game a total of eighteen times.

In addition to Streiff, the coaching staff is heavily compiled of former NFL and NCAA players such as Mike Prior and Darrick Brownlow.

[citation needed] The sculpture Mary is mounted in a limestone niche on the main school building facade.

The statue is a full-length robed representation of the Virgin Mary, standing with her hands outstretched with her palms facing upwards.

[15] Cathedral noted that they would have lost permission to refer to itself as a Catholic school, the ability to celebrate the Sacraments, and its status as an independent nonprofit organization.