Large numbers of Catholics started to arrive in the Western Reserve region of Ohio in the 1830s and were served by visiting priests sent north by the Archdiocese of Cincinnati.

[1] When Pope Pius IX established the Diocese of Cleveland in 1847, he named Louis Amadeus Rappe as its first bishop.

He selected architect Patrick Keely, who designed the building in an ornamental gothic style, and the bishop laid the cornerstone on October 22, 1848.

In 1879, the parish raised sufficient funds to complete interior and exterior decoration and add a spire.

To fund the initial construction, Bishop Rappe was forced to seek donations from sources as far away as New York City and France.

Construction began in 1946, when the old cathedral was enlarged and the brick exterior refaced in orange Tennessee Crab Ochard Sandstone.

[5] The new cathedral contained several new chapels including the Resurrection Chapel, which holds the tombs of former bishops, and the relics of St. Christine of Calixtus (whose relics were discovered in the Catacombs of St. Calixtus outside of Rome), presented to Archbishop Scrembs by Pope Pius XI in 1925.

In keeping with tradition of that time, she had been buried with a small glass vial of her blood, in testament of having given her life for the Faith as a martyr.

[7] On September 4, 1948, Archbishop Hoban with Cardinal Francis Spellman of New York City celebrated a Mass to mark the renovation of St. John's Cathedral.

In 1977, Bishop James Hickey carried out additional renovations due to Vatican II reforms.

In November 2016, Bishop Lennon sent a request to Pope Francis for early retirement owing to declining health.