In 1821, Florida was transferred from Spain to the United States, and in 1824, two Key West men, Joshua Appleby and a man named Snyder, sent an employee, Silas Fletcher, to open a store on Indian Key. The store was to serve wreckers, settlers, and Indians in the upper Keys, and a settlement of primarily Bahamian wreckers and turtlers grew up on the island. By 1829, the settlement was large enough to include a dozen women. Jacob Housman, a wrecker who had a reputation for operating in a "high-handed and often illegal manner", was at odds with the established wreckers in Key West. He moved to Indian Key in 1830, began buying property on the island, and soon became the leader of the community and its chief landlord. He made numerous improvements to the island, spending close to $40,000 on it in four years. His store, the only one on the island, grossed $30,000 a year. As a result of lobbying by Housman, Indian Key acquired an Inspector of Customs in 1832 and a post office in 1834. In 1836, Houseman persuaded the Territorial Legislative Council to split Dade County off from Monroe County, with the upper and middle Keys in the new county and Indian Key as the temporary county seat. Housman also campaigned to have Indian Key made a port of entry, so that salvage from wrecks could be landed there, rather than in Key West, but without success. The Second Seminole War began late in 1835. After the New River Massacre in early 1836, most of the Keys were abandoned, except for Key West, Key Vaca, and Indian Key. Despite fears of attack and sightings of Indians in the area, the inhabitants of Indian Key stayed to protect their property and to be close to any wrecks in the upper Keys. The islanders had six cannons and their own small militia company for their defense. The revenue cutterDexter was based at Indian Key for part of 1838, and after it was withdrawn ships of the Navy Florida Squadron called at Indian Key and established a supply depot there. In 1840, the Navy supply depot was moved to nearby Tea Table Key.
Indian raid
Early in the morning ofAugust 7, 1840, a large party of Spanish-speaking Indians sneaked onto Indian Key. As one man was up, he could raise the alarm after spotting them. Most of the 50 to 70 people living on the island were able to escape, but 13 were killed. The dead included Dr. Henry Perrine, former United StatesConsul in Campeche, Mexico, who was waiting at Indian Key until it was safe to take up a grant on the mainland that Congress had awarded to him. The naval base on Tea Table Key had been stripped of personnel for an operation on the southwest coast of the mainland, leaving only the doctor, his patients, and five sailors under a midshipman to look after them. This small contingent mounted a couple of cannons on barges and tried to attack the Indians on Indian Key. The Indians fired back at the sailors with musket balls loaded in one of the cannons on shore. The cannons' recoil on the barges broke them loose, sending them into the water, and the sailors had to retreat. The Indians burned the buildings on Indian Key after thoroughly looting them. Abandoned by almost all of its civilian population, Indian Key was taken over by the Navy for the duration of the Second Seminole War.
Decline
Indian Key continued to be occupied for a while after the Second Seminole War ended, in 1842. The county seat for Dade County was moved to Miami in 1844, and the upper Keys, including Indian Key, were returned to Monroe County. The 1850 Census found a few families living there, while only two families were left on the island in 1860. In 1856, during the Third Seminole War, the U.S. Army stationed a few men on the island to protect the two remaining families from possible attack by Seminoles. The Keys lost most of their population again during the Civil War, but William Bethel, a wrecker, continued to live on the island from the 1850s until sometime after 1880.