It was put to use in the Atlantic slave trade, making at least two voyages carrying Africans to slavery in the West Indies.

[2] The ship was owned by a consortium of investors, including Thomas Starke, "an experienced slave trader who was part owner of several other slaving vessels and owned five tobacco plantations in Virginia,[3] In 1699 the Henrietta Marie sailed from England on the first leg of the triangular trade route with a load of trade goods, including iron and copper bars, pewter utensils, glass beads, cloth and brandy.

The ship sailed under license from the Royal African Company (which held a monopoly on English trade with Africa), in exchange for ten percent of the profits of the voyage.

The ship then sailed on the second leg of its voyage, from Africa to the West Indies, and in May 1700 landed 191 Africans for sale in Port Royal, Jamaica.

The Henrietta Marie then loaded a cargo of sugar, cotton, dyewoods and ginger to take back to England on the third leg of the triangular route.

After leaving Port Royal the ship headed for the Yucatán Channel to pass around the western end of Cuba (thus avoiding the pirates infesting the passage between Cuba and Hispaniola) and catch the Gulf Stream, the preferred route for all ships leaving the Caribbean to return to Europe.

[5] The Henrietta Marie wreck has yielded more than 7000 objects (and more than 30,000 glass beads), the largest collection of artifacts known from a slave ship.

"The importance of the Henrietta Marie is that she is an essential part of recovering the black experience - symbolically, metaphorically and in reality".

A new exhibition, including a great number of artifacts from the Henrietta Marie will be touring North America, starting in 2019.

[1] In November 2024, the Mel Fisher Maritime Museum opened a new exhibit about the transatlantic slave trade and its connections with the Florida Keys, centered on artifacts from the Henrietta Marie along with materials sourced elsewhere.