European Theater – First through fifth patrols

During her first patrol she carried out reconnaissance duties prior to, and during, the invasion of North Africa. Operating out of Rosneath naval base, Scotland until July 1943, she conducted her next four patrols against the Axis blockade runners in European waters. Barb's fifth patrol terminated 1 July and she proceeded to the Submarine Base, New London, Connecticut, arriving on 24 July.

Pacific Theater – Sixth through twelfth patrols

Following a brief overhaul period at New London, Barb departed for Pearl Harbor where she arrived in September. It was in the Pacific waters that Barb found lucrative hunting and went on to compile one of the more outstanding submarine records of World War II. During the seven war patrols she conducted in the Pacific between March 1944 and August 1945, Barb is officially credited with sinking 17 enemy vessels totaling 96,628 tons, including Un'yō, sunk on 17 September 1944. On 15–16 September Barb rescued 14 Australian and British POW survivors of SS Rakuyō Maru.^[7]

Members of the submarine's demolition squad pose with her battle flag at the conclusion of her 12th war patrol. Taken at Pearl Harbor, August 1945.

The last two war patrols conducted by Barb deserve mention. Under Commander Eugene B. Fluckey, her 11th patrol lasted from 19 December 1944 – 15 February 1945, in the Formosa Straits and East China Sea off the east coast of China, from Shanghai to Kam Kit. During this patrol, Barb sank four Japanese merchant ships and numerous enemy small craft. On 22–23 January Barb penetrated Namkwan Harbor now called Yanpu Wan (沿浦湾)^[8] on the China coast, opposite the Matsu Islands, and wrought havoc upon a convoy of some 30 enemy ships at anchor. Maneuvering in dangerously shallow waters, Barb launched her torpedoes into the enemy group and then retired at high speed on the surface in a full hour's run through uncharted, heavily mined, and rock-obstructed waters. In recognition of this outstanding patrol, Commander Fluckey was awarded the Medal of Honor and Barb received the Presidential Unit Citation.

Upon completion of her 11th patrol, Barb was sent to the U.S. for a yard overhaul and alterations, which included the installation of 5 in (130 mm) rocket launchers at the Captain's request. Returning to the Pacific, she commenced her 12th and final patrol on 8 June. This patrol was conducted along the coasts of the Sea of Okhotsk. For the first time in U.S. submarine warfare, Barb successfully employed rockets, against the towns of Shari, Hokkaido; Shikuka, Kashiho; and Shiritoru on Karafuto.^[9] On 2 July; she also bombarded the garrison on Tyuleny (Kaihyo) Island with her regular armament, destroying the constructions and causing the fire. She next landed a party of carefully selected crew members who blew up a railroad train.

During the night of 22–23 July 1945 these men went ashore at Karafuto, Japan, and planted an explosive charge that subsequently wrecked a train. They were: Chief Gunners Mate Paul G. Saunders, USN; Electricians Mate 3rd Class Billy R. Hatfield, USNR; Signalman 2nd Class Francis Neal Sever, USNR; Ships Cook 1st Class Lawrence W. Newland, USN; Torpedomans Mate 3rd Class Edward W. Klingesmith, USNR; Motor Machinists Mate 2nd Class James E. Richard, USN; Motor Machinists Mate 1st Class John Markuson, USN; and Lieutenant William M. Walker, USNR. This raid is represented by the train symbol in the middle bottom of the battle flag.^[10]