On August 17, 1862, he became the first commanding officer of the cruiser CSS Florida, taking her through a difficult outfitting period during which most of the ship's company was stricken with yellow fever. While in port in Cuba, Commander Maffitt himself contracted the disease. In this condition, Maffitt sailed Florida from Cárdenas, Cuba to Mobile, Alabama. With the way into Mobile Bay blocked by Union warships, Florida braved a hail of projectiles from the blockaders and raced through them to anchor beneath the guns of Fort Morgan. The bombardment from the blockaders was severe and the damage to Florida was so great that Maffitt did not return to sea for more than three months. To prevent his escape, the Union Navy increased the blockading force near Mobile.
Having taken stores and gun accessories the ship lacked, along with added crew members, Maffitt waited for a violent storm before setting out on January 16, 1863. He used trickery to lose six pursuing blockaders. After coaling at Nassau, Bahamas, Florida spent 6 months off North and South America and in the West Indies, with calls at neutral ports, all the while making captures and eluding the large Federal squadron pursuing her. It was during this period that he acquired the nickname "Prince of Privateers" (which was somewhat inaccurate, since he was a naval officer and not an actual privateer.)
Maffitt was promoted to the rank of Commander in May 1863 "for gallant and meritorious conduct in command of the steam sloop Florida." Ill health due to the lingering effects of yellow fever forced him to relinquish command of Florida at Brest, France on February 12, 1864.
In the summer of 1864, after returning to the Confederate States, Maffit was given command of the ironclad ram CSS Albemarle. Under Maffit's command, Albemarle dominated the Roanoke River and the approaches to Plymouth, North Carolina throughout the summer. In September, he was given command of the blockade runner CSS Owl. On October 3, Owl escaped to sea from Wilmington; the blockaders wounded her captain and several crewmen but 9 shots failed to stop them, and Owl arrived in Bermuda on October 24 with a large and valuable cargo of cotton. Maffit made several more successful runs through the Union blockade in Owl before the war ended.
During his service to the Confederacy, Maffitt repeatedly ran the blockade to carry needed supplies and captured and destroyed more than seventy prizes worth $10 to $15 million.
At the end of the war, he refused to surrender his ship to the United States. Instead, he returned Owl to agents in Liverpool. He chose to remain in England, and, after passing the British naval examination, he served for about two years in command of the British merchant steamer Widgeon running between Liverpool and South America. He returned to the United States in 1868 and settled on a farm near Wilmington, North Carolina. In 1870, Maffit commanded a warship for Cuban revolutionaries during the Ten Years' War.
Maffit died in Wilmington in 1886, leaving an unfinished manuscript about piracy in the West Indies. His collected papers are in the library of the University of North Carolina at Chapel Hill.