Gottschalk was born in New Orleans, where he was exposed to a wide variety of musical traditions. His family lived in the Creole quarters of the city, and his Grandmother Buslé and his nurse Sally were both natives of Saint-Domingue. He played the piano from an early age and was soon recognized as a wunderkind by the New Orleans bourgeois establishment. In 1840, he gave his informal public debut at the (then) new St. Charles Hotel.
Only two years later, he left the United States and sailed to Europe, realizing that a classical training would be required to fulfill his musical ambitions. The Conservatoire in Paris, however, initially rejected his application, and Gottschalk only gradually gained access to the musical establishment through friends.
Upon his return to the United States in 1853, Gottschalk travelled extensively; a lengthy trip to Cuba in 1854 marking the beginning of a series of trips to Central and South America. By the 1860s, Gottschalk had established himself as the foremost pianist in the New World. In 1865, however, he was forced to leave the United States as the result of what was regarded as a scandalous affair with a student at the Oakland Female Seminary. He chose to again travel to South America, where he continued to give frequent concerts. During one of these concerts, in Rio de Janeiro on November 24, 1869, he collapsed, probably as the result of food poisoning. Much was made of the fact that, just before his collapse, he had finished playing his romantic piece Morte!!.
Gottschalk never recovered from the collapse and three weeks later, on December 18, 1869, died at his hotel in Tijuca, Rio de Janeiro, Brazil.