When commissioned, the S-42 Class coastal submarine torpedo boat was 225 feet 3 inches in length overall; had an extreme beam of 20 feet 8 inches; had a normal surface displacement of 906 tons, and, when in that condition, had a mean draft of 16 feet. Submerged displacement was 1,126 tons. The hulls were riveted. The designed compliment was four officers and thirty-four enlisted men. The boat could operate safely to a depth of 200 feet. The submarine was armed with four 21-inch torpedo tubes...installed in the bow. Twelve torpedoes were carried. One 4-inch/50 caliber deck gun was installed. The full load of diesel oil carried was 46,363 gallons, which fueled two 600 designed brake horsepower Model 8-EB-15NR diesel engines manufactured by the New London Ship and Engine Company at Groton, Connecticut...which could drive the boat...via a diesel direct drive propulsion system...at 14.5 knots on the surface. Power for submerged propulsion was provided by a main storage battery, divided into two sixty-cell batteries, manufactured by the Electric Storage Battery Company (EXIDE) at Philadelphia, Pennsylvania...which powered two 750 designed brake horsepower main propulsion motors manufactured by the Electro Dynamic Company at Bayonne, New Jersey...which turned propeller shafts...which turned propellers...which could drive the submarine at 11 knots for a short period of time when operating beneath the surface of the sea. Slower submerged speeds resulted in greater endurances before the batteries needed to be recharged by the engines and generators.

After training exercises off the southern New England coast of the United States, USS S-46 (SS-157) transited to the Panama Canal Zone to join Submarine Division 19. Arriving at the submarine base at Coco Solo on 26 September 1925, the submarine commenced a schedule of local operations, both from Coco Solo and from Balboa, which were interrupted only for semi-annual extended training cruises and annual fleet problems in the Caribbean Sea and Pacific Ocean. Repairs and overhauls were performed at Balboa.

In 1927, SubDiv19 was transferred to the Battle Fleet and based at San Diego, with Mare Island as home-yard for its boats. S-46 departed Panama on 11 June; arrived at San Diego on the 31st; then proceeded, via Mare Island to Pearl Harbor to participate in tactical exercises with other Battle Fleet submarines. During the latter part of August, she participated in the search for missing Dole Flight pilots; and, at the end of the month, she headed back to San Diego for two months of local operations. In December she returned to Mare Island for an overhaul; and, in June 1928, she resumed operations out of her home port. In November, despite many attempts to improve design limitations of the "S-42"-class, the maximum speed set for S-46, and others of that class, was reduced to 10.5 knots to eliminate excessive vibration and accompanying engineering problems at higher speeds.

S-46 remained based at San Diego until December of 1930, when her division was transferred to Pearl Harbor. There, for the next five years, she participated in training operations with her division, now SubDiv11 and with other fleet units, and spent extended periods of time in port as a unit of Rotating Reserve Division 14. In the spring of 1936, after participating in Fleet Problem XVII, she returned to Coco Solo, where she had again been homeported.

Still in SubDiv11, S-46 remained based at Coco Solo through the end of the decade, operating on a schedule similar to that of her first tour in the Canal Zone. After September 1939, however, operations were confined to the canal approaches. In the spring of 1941 SubDiv11 was ordered to New London to assist in patrols off the New England coast and in Submarine School training operations. En route north, S-46 underwent overhaul at Philadelphia, and, in August, she commenced operations out of New London. In October, she shifted to Ordnance Island, Bermuda; and, in December, after the attack on Pearl Harbor, she returned to the Panama Canal Zone.

During the next six weeks, she conducted two defensive war patrols in the approaches to the canal, then prepared to cross the Pacific. On 5 March 1942, she headed west with her division, now SubDiv53. In mid-April, the World War I-design submarines arrived at their new base, Brisbane, Australia, and joined TF-42. On 13 May, S-46 departed on her third first-offensive war patrol.

On leaving Moreton Bay, the S-boat conducted sound training exercises with an Australian escort, then continued on. On the 15th, the ship's cook was discovered to have the mumps. On the 16th, the boat put into Townsville, and, on the 22nd after hospitalizing sick crew members and disinfecting messing, berthing, and working areas, she set a course for her patrol area, New Britain.

On the 26th, S-46 passed Rossel Island. On the 31st she began her transit of St. George's Channel, favoring the New Ireland coast. That night, she hunted in the approaches to Rabaul and between there and the Duke of York Islands. On the night of 1 and 2 June, while patrolling on the Rabaul-New Hanover line, she was spotted by two Japanese destroyers, but no attacks were made. On 3 June, the submarine began hunting along the northern coast of New Britain. On the 4th west of the Willaumez Peninsula, she developed motor trouble and turned for Vitiaz Strait, one of the few areas for which she carried charts. On the 5th, she entered the strait; and, on the 7th, she commenced patrolling between Cape Cretin and the south end of Dampier Strait. Two days later, she was ordered to intercept Japanese destroyers thought to be heading for Lae on an estimated course which would take them north of Woodlark Island.

Moving into the area, S-46 sighted no enemy ships and resumed her patrol in the Cape Cretin area. On the 11th, she headed for Brisbane. On the 19th, an auxiliary air compressor jammed, the motor burned out and the resulting smoke added further habitability problems to the already hot and humid condition of the boat. On the 21st, S-46 reached Brisbane.

On her 4th war patrol, 20 July to 15 August, S-46 hunted in the Solomons. On her 5th patrol 11 September to 11 October, she resumed a defensive role and patrolled in an area east of Normandy Island, off Papua, in anticipation of a major enemy attack of Milne Bay.

In early November, S-46 started back across the Pacific. On 7 January 1943, she arrived in the Panama Canal Zone; and, in early February, she continued on to Philadelphia. There, from April to mid-June, she received extensive repairs and alterations. She then returned to Panama; retransited the canal and proceeded to San Diego for further yard word. In mid-September, she moved north to Unalaska in the Aleutians.

Based at Dutch Harbor, S-46 ranged westward into the Kurils during her last two war patrols, October, November 1943 and December 1943 - January 1944. During the first, she damaged an enemy oiler in the Paramushiro area; during the second, she was scoreless. On returning to Dutch Harbor after her last war patrol, she was assigned, with others of her class, to antisubmarine training activities.

For the remainder of the war; S-46 provided training services in the Aleutians, in the Hawaiian Islands and off the coast of California. In the latter area from January 1945, she operated under the Commander West Coast Sound School, San Diego. After the cessation of hostilities in August, she was ordered to San Francisco for inactivation; and, in late September, she moved up the bay to Mare Island.

S-46 was decommissioned on 2 November 1945. Her name was struck from the Navy list two weeks later, and her hulk was sold for scrapping to the Salco Iron and Metal Co., San Francisco, in November 1946.