S-44′s keel was laid down on 19 February 1921 by the Bethlehem Shipbuilding Corporation's Fore River Shipyard in Quincy, Massachusetts.

In late August, she departed New London, Connecticut, for Panama and on 5 September arrived at Coco Solo to join Submarine Division (SubDiv) 19.

From that time to December 1930, she operated out of San Diego with her division, interrupting exercises off southern California twice for fleet problems in Hawaiian waters.

In the spring of 1941, as American involvement in World War II increased, the Panama S-boats were ordered back to the east coast for overhaul.

Starting across the Pacific in early March, the boats reached Brisbane in mid-April, and within ten days, S-44 was on her first war patrol.

Three days later, her port engine went out of commission, but 36 hours of hard work and ingenuity put it back in operation.

On 29 April, she began running submerged during the day and surfacing at night to recharge batteries and allow fresh air into the non-air-conditioned boat.

Just three minutes later the enemy aircraft dropped a bomb which exploded close to the submarine, bending the holding latch to the conning tower and allowing in 30 gallons of sea water.

The number-one periscope was thought to be damaged; but when the submarine surfaced a Japanese seaman's coat was found wrapped around its head.

The next day, she sighted a convoy off Cape St. George, but heavy swells hindered depth control and speed, and prevented her from attacking.

On 7 August, the American offensive opened with landing of the 1st Marine Division on the beaches of the Solomon Islands of Guadalcanal and Tulagi.

On 9 August, off Savo Island, Cruiser Division 6 of the Imperial Japanese Navy had inflicted one of the worst defeats of the war on American and Australian surface ships.

On 22 September, she began surfacing only at night, and, two days later, took patrol station off New Georgia to interdict Japan's Faisi-Guadalcanal supply line.

That night, further repairs were made while the ship was surfaced off Santa Isabel Island; and, by midnight, the S-boat was en route back to her patrol area.

In early January 1943, she transited the Panama Canal, then moved across the Caribbean Sea and up the Atlantic seaboard to Philadelphia.

There, from April to June, she underwent overhaul; and, in July, she retransited the Canal en route to San Diego and the Aleutian Islands.

One day out, while en route to her operating area in the northern Kuril Islands, she was spotted and attacked by a Japanese patrol plane.

A pillow case was raised from the forward battery room hatch as a flag of surrender, but the Japanese shelling continued.