Prior to the establishment of the diocese in 1847, Cleveland was first, part of the Diocese of Bardstown, Kentucky created in 1808. In 1821 the Diocese of Cincinnati was formed and encompassed the entire state of Ohio.

As northeast Ohio began to develop, the oldest parish community in the present Diocese of Cleveland was founded in 1827, SS. Peter and Paul Parish in Doylestown in Wayne county. Soon after, the first parish community in Summit County, St. Joseph Parish was established in Cuyahoga Falls. The first Catholic Church in Cleveland was St. Mary of the Flats which was built in 1838.

In 1848 ground was broken at Superior Avenue and Erie Street (East 9th) for construction of St. John Cathedral which was dedicated on November 7, 1852.

In 1850, the Ursuline sisters arrived in Cleveland and established a convent and school. In 1865, St. Vincent Charity Hospital in Cleveland was opened as the result of a unique cooperative effort between the Diocese and city officials as the hospital was placed under the care and is still maintained by the Sisters of Charity of St. Augustine.

The Cleveland Diocese across the northern tier of Ohio was changed in 1910 with the creation of the Diocese of Toledo which encompasses 19 counties in northwestern Ohio. Much later, in 1943, the Diocese of Youngstown was formed and included six counties in the northeast corner of the state.

A significant development within the Cleveland Diocese occurred in 1911 when the Board of Charities was organized, eventually leading to the establishment of Catholic Charities of Diocese of Cleveland, now recognized as one of the largest Charitable operations in the world.

1942 through 1966 marked a time of unprecedented growth in the Diocese as the Catholic population grew from 546,000 to 870,000 by 1966. Sixty-one new parishes, 47 new elementary schools and 12 new high schools were built. Borromeo Seminary was also opened with high school and college undergrad classes in 1953.

In 1964, the Diocese of Cleveland established its Diocesan Mission in El Salvador which still operates and is staffed by Cleveland personnel today.

In 1980, the tenure of Cleveland's longest serving Bishop and native, Most Reverend Anthony M. Pilla began. His Episcopacy included the presidency of the National Conference of Catholic Bishops in 1995.

Most Reverend Richard G. Lennon was installed as Cleveland's 10th Bishop in May of 2006. Bishop Lennon continued the Diocese's reconfiguration process which has seen a reduction in parishes to the current 174. The changes were based on a reduction in the number of practicing Catholics and the outmigration of the Catholic population to the suburban and exurban areas of the eight counties of the Diocese but with an emphasis on evangelization through the creation of more vibrant parishes.