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The back portion of the house was built first, with little attention to aesthetics. Gamble's priority was to get the house built to provide protection from the elements and the possibility of attack by Indians. After quickly completing the back portion, Gamble added on the front section of the mansion, with far more focus on appearance. The columns in the front are an example of the Doric Revivalist Vernacular style, and are constructed out of Tabby, which is a mixture of locally available materials including burnt oyster shells which acts as a sort of mortar, holding the mixture together. Gamble accumulated almost 3,500 acres, but natural disasters and a fickle sugar market drove him into debt by 1856. 

He sold the property in 1859 to satisfy the debts and moved to north Florida with all of the furniture from the mansion. When he arrived in north Florida, Gamble placed the furniture in a warehouse, which burnt down 13 hours later. Consequently, none of the furniture in the mansion is original, although much of it is from the time period and represents the type of furniture that would have likely been in the house.

After Gamble left, Captain Archibald McNeill, a famous Confederate blockade runner, moved into the mansion. In May of 1865, the Confederate Secretary of State, Judah P. Benjamin took refuge in the home after the fall of the Confederacy. After falling into disrepair in the early 1900s, the house and 16 acres  were purchased by the United Daughters of the Confederacy in 1925 and donated to the State of Florida.

The sugar mill at Gamble plantation was destroyed during the Civil War and large segments of the brick walls of the destroyed sugarhouse were removed in subsequent years. The mill site was acquired by the state in 2002 in hopes of preserving what remained of this important component of the Gamble plantation. Vegetation has been removed from around the ruins and a fence has been erected to allow viewing of the site while providing for its protection. Today the mansion is furnished in the style of a successful mid-19th century plantation. Guided tours of the house are given daily,

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In 1843, Major Robert Gamble, Jr. established a sugar plantation along the Manatee River, a region then remote from civilization. The Gamble mansion was built between 1845 and 1850 and was part of an extensive plantation where sugar cane was cultivated and refined into sugar.