Constructed in 1822 under the direction of architect Simon Bernard, Fort Wood was thought to be impregnable to enemy troops attacking in the narrow straits of lakes Borgne and St. Catherine. In 1851, the fort was renamed Fort Macomb to honor Alexander Macomb, a field commander lauded for his actions during the War of 1812.

Fort Macomb is a Third System fort. Third System forts, erected to protect the nation's waterways from attack, were made of superior materials and usually housed more cannons than their earlier First and Second System counterparts (see Fort Petite Coquilles).

Fort Macomb features the same general design as Fort Pike, located just nine miles away. However, unlike Pike, Macomb is in poor condition today due to the encroachment of Lake Catherine.

Fort Macomb was never used for offensive purposes. During the Second Seminole and Mexican Wars, the fort was a staging area for supplies. During the Civil War, Confederate forces seized control of the fort in January of 1861. Union troops regained the fort and used it for training exercises and barracks in 1862. The First Louisiana Native Guard, one of the first all-black regiments to fight in the Union Army performed guard duty at Fort Macomb during the American Civil War. The First Louisiana Native Guard was comprised of self-emancipated men and free men of color.

The fort caught fire in 1867 and the government abandoned the site. The government decommissioned the fort by 1871.

In recent years, Fort Macomb has played host to several film projects including HBO's True Detective, NCIS, and Beyonce's Lemonade.