The current bishop, William Medley, was the pastor of Saint Bernadette Parish of the Archdiocese of Louisville prior to his consecration which took place February 10, 2010.

Among the early missionaries was Stephen Badin who set out on foot for Kentucky on September 3, 1793, sent by Bishop John Carroll of the Diocese of Baltimore.

For the next 14 years Badin traveled on foot, horseback and boat between widely scattered Catholic settlements in Kentucky and the Northwest Territory.

In 1808, Pope Pius VII erected the Diocese of Bardstown, covering Kentucky and most of the Northwest Territory.

Cotton had first planned to establish his cathedral in Henderson, Kentucky at Holy Name of Jesus Catholic Church, but then changed it to Owensboro.

[6] In early 1940, Cotton began the collection of relief supplies for refugees from World War II in Europe.

[15] In October 2018, the diocese permanently removed Reverend Gerald Baker from active ministry after determining that sexual abuse accusations against him were credible.

He had been accused by three minors in 2016 when he was serving at St. Mary of the Woods Parish; at that point, the diocese put Baker on temporary suspension.

[15][16] In March 2019, the diocese temporarily suspended Reverend Ed Bradley after he was accused sexual abuse of a minor.