While she was conducting shakedown training from New London, she suffered damage on 28 February 1942 when a PBY-5A Catalina amphibian of U.S. Navy Patrol Squadron 73 (VP-73) mistook her for a German U-boat and bombed her.

The submarine attacked the cargo ship Seia Maru four times 30 April – 1 May off Eniwetok, but due to faulty torpedoes was not able to sink her.

As the Japanese converged on the Solomon Islands, Truk became a busy shipping point and a fertile ground for submarine operations.

One of the first submarines to operate in the Truk area, she now joined in the undersea blockade of that important base, in an attempt to cut its supply lines to Japan.

Next morning the submarine took periscope photographs of Truk, and steamed to the New Ireland area, attempting to intercept Japanese fleet units retiring from the Solomons.

The submarine encountered surface opposition in the area, but evaded a destroyer attack 20 August and set course back to Midway.

En route on 26 August she used her deck gun to destroy a large Japanese sampan of from 50 to 100 tons at 5°13'N, 160°-17'E;[8] she arrived Midway 1 September 1942.

She fired three torpedoes at cargo ship Takusei Maru 14 October, scored three hits, and watched her sink in the space of 6 minutes.

Greenling cleared Brisbane 17 May to conduct her sixth war patrol, in the Solomons–New Guinea area, long the scene of bitter sea and land fighting.

She ended the old year with a late night attack, sinking freighter Shōhō Maru, reconnoitred Wake Island, and returned to Midway 28 January 1944.

Closely watched by enemy aircraft, Greenling recorded no torpedo sinkings, though she sank a trawler with gunfire 8 August north-east of Luzon, Philippines in position 19°50'N, 119°58'E.

There it was decided to send her to the United States, and Greenling steamed via Pearl Harbor, San Francisco, and the Panama Canal to Kittery, Maine.