During the American Civil War, Semmes was captain of the cruiser CSS Alabama, the most successful commerce raider in maritime history, taking 65 prizes.

After Alabama seceded from the Union, Semmes was offered a Confederate naval appointment by the provisional government; he resigned from the U.S. Navy the next day, February 15, 1861.

[9] After appointment to the Confederate Navy as a commander and a futile assignment to purchase arms in the North, Semmes was sent to New Orleans to convert the steamer Habana into the cruiser/commerce raider CSS Sumter.

[10] In June 1861, Semmes, in Sumter, outran the USS Brooklyn, breaching the Union blockade of New Orleans, and then launched a brilliant career as one of the greatest commerce raider captains in naval history.

[11] Semmes' command of CSS Sumter lasted only six months, but during that time he ranged wide, raiding US commercial shipping in both the Caribbean Sea and Atlantic Ocean; his actions accounted for the loss of 18 merchant vessels, while always eluding pursuit by Union warships.

[12] US Navy vessels maintained a vigil outside the harbor until she was disarmed and sold at auction in December 1862, eventually being renamed and converted to a blockade runner.

He then was ordered to the Azores to take up command and oversee the coaling and outfitting with cannon of the newly built British steamer Enrica as a sloop-of-war, which thereafter became the Confederate commerce raider CSS Alabama.

[14] Alabama finally sailed back to the Atlantic and made port in Cherbourg, France, for a much-needed overhaul; she was soon blockaded by the pursuing Union steam sloop-of-war USS Kearsarge.

[15] Alabama's much-too-rapid gunnery and misplaced aim, combined with the deteriorated state of her gunpowder and shell fuses, enabled a victory for both of Kearsarge's 11-inch (28 cm) Dahlgren smoothbore cannon.

[15] After receiving a fatal shell to the starboard waterline, which tore open a portion of Alabama's hull, causing her steam engine to explode from the shell's impact, Semmes was forced to order the striking of his ship's Stainless Banner battle ensign and later to display a hand-held white flag of surrender to finally halt the engagement.

As his command sank, the wounded Semmes threw his sword into the sea, depriving Kearsarge's Winslow of the traditional surrender ceremony of having it handed over to him as victor.

He was promoted to rear admiral in February 1865, and during the last months of the war he commanded the boxed-in James River Squadron from his flagship, the heavily armored ironclad CSS Virginia II.

With the fall of Richmond, in April 1865, Semmes supervised the destruction of all the squadron's nearby warships and thereafter acted as a brigadier general in the Confederate States Army, the implication being that he was appointed to that grade.

[18] Historians John and David Eicher show Semmes as appointed to the grade of temporary brigadier general (unconfirmed) on April 5, 1865.

[18] Historian Bruce Allardice notes that Semmes was vague about this appointment in his memoirs and considered his naval rank of rear admiral to be the equivalent of a brigadier general.

Semmes and the Naval Brigade were surrendered to Union Major General William T. Sherman with Johnston's army at Bennett Place near Durham Station, North Carolina; he was subsequently paroled on May 1, 1865.

[30] In 1998, William Butcher identified a possible link between the Birkenhead, England-built CSS Alabama and Captain Nemo's Nautilus from the 1869 Jules Verne novel Twenty Thousand Leagues Under the Sea.

Butcher said, "The Alabama, which claimed to have sunk 75 merchantmen, was destroyed by the Unionist Kearsarge off Cherbourg on 11th June 1864….This battle has clear connections with Nemo’s final attack, also in the English Channel.