On 17 December 1799, during the Quasi-War with France, Enterprise departed the Delaware Capes for the Caribbean to protect United States merchantmen from the depredations of French privateers.

[4] She left Curacao around the end of January 1800 and on 3 February received orders from Commodore Thomas Truxtun to sail home with dispatches.

[5] Returning to the West Indies, on 23 April 1800, she had a brief engagement with a Spanish packet that opened fire on her, but broke off the fight upon realizing that the ship was a neutral.

[16][17] On 6 December, she fought a night engagement with a privateer lugger that started one league off St Bartholomew's, ending close to shore when she broke off rather than risk being wrecked on the unfamiliar island.

Enterprise's first action came on 1 August 1801 when, seven leagues west of Malta,[25] she defeated the 14-gun Tripolitan polacca[26] corsair Tripoli, after a fierce but one-sided battle.

Yesterday captain Sterret, commander of the schooner Enterprize, part of the Mediterranean squadron, arrived here, with dispatches for the Secretary of the Navy.

Captain Sterret is bearer of dispatches from commodore Dale, which exhibit a detailed account of the proceedings and situation of the Mediterranean squadron.

When for the third time, this treacherous attack was made, captain Sterret gave orders to sink the Tripolitan, on which a scene of furious combat ensuded, until the enemy cried for mercy.

When we compare this great slaughter, with the fact that not a single individual of the crew of the Enterprise was in the least degree injured, we are lost in surprise at the uncommon good fortune which accompanied our seamen, and at the superior management of Captain Sterrett.

On the arrival of the Tripolitan ship at Tripoli, so strong was the sensations of shame and indignation excited there, that the Bey ordered the wounded captain to be mounted on a Jack Ass, and paraded thro' the streets as an object of public scorn.

So thunderstruck were the Tripolitans at this event, and at the apprehended destruction of their whole marine force, that the sailors, then employed at Tripoli on board of cruisers that were fitting out by the government, all deserted them, and not a man could be procured to navigate them.

[29] On 16 October 1802 at Leghorn, her supply barge capsized and was lost along with a midshipman and three crewmen; the survivors were rescued by a boat from USS Constellation.

craft ashore on the coast of Tripoli during an exchange of fire with shore batteries, then fought off an attack by Tripolitan gunboats the next day.

[31] For the next month, Enterprise and other ships of the squadron cruised inshore, bombarding the coast and sending landing parties to burn small enemy vessels.

[32][33] On 23 December 1803, after a quiet interval of cruising, Enterprise joined with frigate Constitution to capture the Tripolitan ketch Mastico.

[35][36] Decatur and volunteers from Enterprise carried out their mission almost perfectly, destroying the frigate and depriving Tripoli of a powerful warship.

[38] Enterprise continued to patrol the Barbary Coast until July 1804, when she participated in coordinated American naval bombardments and attacks on the city of Tripoli over a period of several weeks, bringing the war to an end.

Repaired at the Washington Navy Yard, Enterprise was recommissioned there in April 1811, then sailed for anti-piracy operations out of Savannah, Georgia, and Charleston, South Carolina.

The brigs opened fire on each other, and in a closely fought, fierce, and gallant action which claimed the lives of both commanding officers, Enterprise captured Boxer and, under the guidance of her new captain Samuel Drinkwater,[39] took her into nearby Portland, Maine, where commandant Edward McCall oversaw a joint funeral for Lieutenant William Burrows of Enterprise, and Captain Samuel Blyth of Boxer, both well-known and highly regarded in their respective naval services.

In 1818, she was under the command of Lieutenant Lawrence Kearny of the New Orleans Squadron, who evicted the pirate Jean Lafitte from Galveston, Texas.

An attack on Cape Antonio, Cuba in October 1821 resulted in the rescue of three vessels taken by pirates, and the breaking up of an outlaw flotilla reputedly commanded by James D. Jeffers, aka "Charles Gibbs".

Enterprise's career ended on 9 July 1823, when she stranded and broke up on a reef near Little Curacao Island in the West Indies.