The faith community of St. Luke's originated in the home of Francis Eppes (1801–1881), who was the grandson of Thomas Jefferson and an ardent Episcopal churchman and lay reader.

The Eppes, Shine, Summerlin, Westcott, and Greetham families formed a faithful group which became the nucleus for the formation of St. Luke's Mission, which formally organized in 1881 and achieved parish status in 1884.

Charles T. Gaskell was dean from 1971 to 1973, the nave was renovated, the choir gallery was built over the narthex and an 88-rank pipe organ was installed.

The completed cathedral includes an apse, ambulatory, priests and working sacristies, a bell tower and the St. Mary Chapel.

In addition to being cultural ambassadors of the United States and the City of Orlando, they have toured around the world (most recently in England).

In June 2014, they participated in the inaugural American Music Performance Nationals for Children's & Youth Choirs in New York City at Carnegie Hall.