On 5 April Scorpion departed Pearl Harbor for her first war patrol, a hunting and mining mission off the east coast of Honshû. On 19 April, she reached the mining area near Nakaminato. During the afternoon she reconnoitered the coast and in the evening she laid her naval mines, then retired to deep water. On 20 April she sank her first enemy ship, a 1934-ton converted gunboat. On 21 April, prior to 01:00, she fired on and destroyed her first sampan in surface action, then moved up the coast to observe the fishing grounds, shipping lanes, and coastline of the Shioya Saki area. On the night of 22 April she destroyed three more sampans with gunfire and continued north, toward Kinkasan To.
With the absence of shipping along the coastal lanes she moved seaward and on 27 April sighted a convoy of four freighters escorted by a destroyer. At 04:59, she launched four torpedoes at the first and largest merchantman; two at the second; then dived and rigged for depth charging. At 05:05, the destroyer dropped her first depth charges. A half-hour later, the Japanese warship broke off her search for Scorpion to aid the stricken passenger-cargo ship. While Scorpion escaped with slight damage, the 6380-ton merchant vessel sank.
On 28 April, Scorpion received orders home. En route on 29 April, she sighted and engaged a 100-ton patrol vessel, which she left burning to the waterline. On the morning of 30 April, she stalked, fired on, and finally torpedoed and sank a 600-ton patrol ship. During the hour and three-quarters fight, however, Scorpion received her first casualty. Lieutenant Commander R.M. Raymond, on board as prospective commanding officer, was hit and killed by gunfire.
Soon after the patrol vessel went down, an enemy plane appeared. Scorpion submerged; survived the plane's depth charges and continued toward Midway Island and Pearl Harbor, arriving on 8 May.