The fort was named in honor of Commodore Edward Preble, who led a squadron of American warships during the Barbary Wars.

In October 1808, Dearborn ordered a company of the Regiment of Light Artillery under Captain Joseph Chandler to occupy the fort and instructed them to do whatever was necessary to enforce the Embargo Act against embargo-breaking ships.

[3] The embargo was an attempt to punish Britain and France for actions against US shipping by prohibiting exports to them; it cut off much of New England's income and was highly unpopular.

The embargo was finally lifted in March 1809 when President James Madison took office, but the situation eventually led to the War of 1812.

When Winfield Scott and other American soldiers returned from British imprisonment in Quebec, they were landed at Fort Preble.

Soldiers from the fort saw action when Confederate Army raiders entered Portland Harbor on June 26, 1863, aboard a captured ship named Archer.

The Confederates captured the United States Revenue Cutter Caleb Cushing the next day, and attempted an escape in an action known as the Battle of Portland Harbor.

Light wind made escape impossible and the Confederates abandoned the Caleb Cushing in boats after setting the ship on fire.

[5] On 15 July 1863, Billy Laird, a private in the 17th Maine Regiment, was executed by firing squad at Fort Preble after being charged with desertion.

[4][7] In the 1870s Fort Preble was modernized under the supervision of Army engineer Thomas Lincoln Casey, who is best known for overseeing the completion of the Washington Monument.

A reserve regiment to supplement the regular forces in wartime was also formed, the 240th Coast Artillery of the Maine National Guard.

[10] All remaining mortars were scrapped in 1942; Fort Preble was superseded by new defenses centered on Battery Steele on Peaks Island.

Some of Fort Preble's original early 20th Century brick buildings (including officers' quarters, barracks and a fire station) remain and are in a good state of preservation.