While serving aboard the wooden frigate U.S.S. Cumberland, Selfridge had his first encounter with an ironclad. On March 8, 1862, the C.S.S. Virginia claimed the U.S.S. Cumberland as one of her first victims. While shells from the rebel ironclad penetrated the Cumberland's fragile hull and exploded among her crew, shots merely bounced off the Virginia's 4" thick armor. The Cumberland sank after the Virginia rammed her starboard side, taking two-thirds of her crew with her. Lieutenant Selfridge, who was in charge of the forward battery of six guns, saved himself by jumping from a gunport and swimming to a nearby launch.

Selfridge wrote of the incident:

"Furious over the loss of the ship in which I had taken such intense pride, shivering with cold from soaking wet and scanty clothing, the reaction from the long endured, frightful, experiences of battle impelled me to tears, and I sobbed like a child."

This was the beginning of what Proved to be a dramatic naval career for the young lieutenant.

Selfridge had the unique opportunity to serve as captain of the Monitor for four days following the famous ironclad battle, but was replaced with a permanent commander. He then spent two weeks in command of an experimental submarine called the Alligator. In August 1862, Selfridge was promoted to lieutenant commander and became the third captain of the ironclad gunboat U.S.S. Cairo. George Yost, the Cairo's youngest crew member, noted the arrival of the twenty-six year old commander in his journal.

"Friday Sept. 12th. At 1 P.M. we received on board Commander Selfridge (of the U.S. Frigate Cumberland as our Captain... at 2 P.M. Capt. Selfridge made us a little speech in which he declared his intention of enforcing a rule heretofore unnoticed which was not to allow any profane swearing whoever broke this rule was to be severely punished."

During the first three months of Selfridge's command, the Cairo spent much of her time patrolling the Mississippi River. In November of 1862, the Cairo was detailed to an expedition being formed to attack Vicksburg. As a preliminary to this expedition, the ironclad was ordered to ascend the Yazoo and clear the river of Confederate torpedoes, or underwater mines. Shortly after 11:00 a.m. on December 12, 1862, U.S.S. Cairo struck two of these "infernal machines" and sank in twelve minutes. Selfridge wrote of the incident in his Memoirs:

"Two explosions occurred in quick succession, which seemed to lift vessel out of the water, and notwithstanding every effort to keep her afloat, she sank In twelve minutes, leaving nothing but the tops of her chimneys showing above six fathoms of water. All hands were saved."

Although no lives were lost with the Cairo, the sinking of the Union ironclad earned Selfridge considerable criticism. Admiral Porter accused Selfridge of disobeying orders and added, "My own opinion is that due caution was not observed." The admiral, however, apparently impressed with Selfridge's aggressiveness, later withdrew his censure: "I can see in it nothing more than one of the accidents of war arising from a zealous disposition on the part of the commanding officer to perform his duty."

Selfridge was then placed in command of the timberclad gunboat Conestoga. On March 8, 1864, exactly two years after the loss of the Cumberland, the Conestoga collided with the steamer Genera/ Price and sank in about four minutes. "Thus for the third time in the war, I had my ship suddenly sunk under me, Selfridge wrote. He added, "It is a strange coincidence that the names of these three ships all begin with the letter "C." Admiral Porter, in some disgust, said, "Well, Selfridge, you do not seem to have much luck with the top of the alphabet.. He was then given command of the ironclad Osage, far from the "top of the alphabet.

Selfridge finished his Civil War career in command of the gunboat Huron on an expedition against Ft. Fisher. He was twenty-nine years old when the war ended. The young naval officer spent the entire Civil War period on active service, most of it in combat zones. A fellow officer wrote, Selfridge "has lived a good while for a young man." In 1869, Selfridge was promoted to the rank of commander and spent the remainder of his naval career traveling the world.

Thomas O. Selfridge Jr. retired with the rank of rear-admiral in 1898, ending a career of forty-seven years in the Navy. Selfridge died two days before his eighty-eighth birthday on February 4, 1924 in Washington, D.C.