By the early 1700's, the Spanish Franciscans had established a network of 40 missions in Northern and Central Florida, with 70 priests ministering to over 25,000 Native American converts.

[2] However, raids by British settlers and their Creek Native American allies from the Carolinas eventually shut down the missions.

Part of the reason for the raids was that the Spanish colonists gave refuge to enslaved people who had escaped the Carolinas.

After the end of the French and Indian War in 1763, Spain ceded all of Florida to Great Britain for the return of Cuba.

[8] Four years later, Pope Pius VIII in 1829 erected the Diocese of Mobile, giving it jurisdiction over the Florida Panhandle west of the Apalachicola River.

Pope Benedict XVI named Monsignor Gregory Parkes from the Diocese of Orlando as the fifth bishop of Pensacola-Tallahassee in 2012.

Three sisters in an October 1997 article in the Tallahassee Democrat publicly accused Revered David McCreanor of St. Louis Parish of having sexual affairs with them when they were teenagers in the 1980s.

[22] The Vatican immediately asked Bishop Robert N. Lynch of the Diocese of St. Petersburg to go to Palm Beach, Florida, to hear Symons' confession.

[23] In June 1998, Lynch announced that John Paul II had accepted Symons' resignation as bishop of Palm Beach.

In 2005, the diocese settled a lawsuit brought by Paul Tugwell, who had claimed an attempted sexual assault by Bowles when he was a minor.

Tugwell alleged that Bowles unsuccessfully demanded oral sex from him on a trip to Calloway Gardens at Pine Mountain, Georgia, in 1971.

[25] The diocese in August 2018 removed Reverend Edward Jones from two parish positions after receiving a credible accusation of sexual abuse.

[27] A Pensacola man in July 2023 claimed that he had been sexually abused by Monsignor James Flaherty between 2011 and 2012, starting when the boy was in sixth grade.