The first inhabitants of St. John were the Taino Indians. The Tainos were skilled farmers and craftsmen who specialized in creating artifacts from stone, wood and ceramics. They traded their artifacts and agricultural products with the natives of other islands, and eventually, the Europeans.

After Columbus arrived on his second voyage, France colonized the islands and turned the primary industries to sugar cane and rum. Sugar was a valuable crop to Europeans who had been exposed to coffee, for they considered the new beverage far too bitter to drink without a sweetener. France's colonies in the Virgin Islands were ideal for growing the crop because of its temperate climate. A shortage of laborers was created when the small farms were merged into huge plantations, and in 1674, slavery was introduced to the islands. The first slaves were the Carib Indians, but they proved to be too susceptible to the European diseases. Next, indentured servants were used on the plantations, and finally, the Africans were brought in because they were thought to be the only ones who could work the long hours in the hot climate.

St. John also has the distinction of being the site of the first slave revolt in the Virgin Islands. Unrest amongst the slaves existed as early as 1722, particularly on St. John where the working conditions were particularly abyssmal. However, the slaves put up with the conditions until 1733. In that year, many slaves died of starvation which was caused by a year of hurricanes, insect plagues, and drought. On November 23, 1733, slaves attacked the fort in Coral Bay and killed all but one of the soldiers, The lone survivor managed to escape the fort and carry warn the governor on St. Thomas. The rebelling slaves raised a flag of their own and shot the fort's cannon three times, which signaled an island-wide insurrection. Only 146 of the 1048 slaves on St. John were actually actively involved in the revolt, they managed to kill one-third of the white population and severely damage over half of the 92 plantations. Six months later the French re-took the island and most of the slaves-in-hiding committed suicide. The slaves that did surrender were tortured and killed, even though they had been promised pardons.

In 1733 St. John was purchased by the Danes and it became part of the Danish West Indies along with St. Thomas and St. Croix. Under Danish rule, the economy of the Virgin Islands were based again on the plantation systems, which continued to be worked by the field slaves.

The first seat of government in St. John was Coral Bay. Later, it was moved to Cruz Bay because that was where all the judges and government officials lived.

It wasn't until 1848 that Captain Mourier arrived at St. John from St. Thomas with the announcement of the abolition of slavery. In order to prevent all of the workers from leaving St. John, the chief constable issued a public notice making it illegal to transport "persons of the working class" away from the island. With slavery abolished, most of the Danes left the island and the sugar plantations deteriorated. The former slaves staked their own land, built homes, and went back to fishing and small farming. Denmark sold all of the Virgin Islands to the United States in 1917. The reason the United States bought them for $24 million was to prevent enemy strongholds in the Carribean.

Lawrence Rockerfeller purchased Caneel Bay, Trunk Bay and Hawkes Nest in the early 50s. He subsequently gave it all to the federal government to be used as a US National Park. In 1956, the park was created. With the free port status and the world increase in tourism, St. John, along with the rest of the U.S. Virgin Islands, became a desired vacation destination.