As a fine example of Greek revival Architecture, Trinity Episcopal Church was incorporated by an Act of the Legislative Council of the Territory of Florida on Feb 11, 1837. The building was one of the earliest prefabricated buildings in America. The framework was shipped by schooner from New York and assembled in Apalachicola with wooden pegs. It is the oldest operating church in the state.

Famed American botanist, Alvin Wenthworth Chapman(1809–1899) settled in Apalachicola in 1847. In 1860, he published his major work, Flora of the Southern United States. The Florida State Parks operate the Chapman Botanical Garden which is named in his honor as part of Orman House Historic State Park.

In 1849, Apalachicola physician Dr. John Gorrie (1802–1855) discovered the cold-air process of refrigeration and patented an ice making machine in 1850, as the result of experiments to lower the temperatures of fever patients, laying the groundwork for modern refrigeration and air-conditioning. The city has a monument to him, and a replica of his ice machine is on display in John Gorrie Museum State Park.