Steaming to New York, the cruiser departed on 10 January 1931 for the Pacific, and after stopping at the Panama Canal and the Hawaiian Islands, arrived at Manila on 22 February.

She landed Marine and Navy gun platoons to help stabilize the situation and remained in the area, with the exception of a good will cruise to the Philippines in March and one to Japan in May 1933, until being relieved by Augusta on 17 November 1933.

The cruiser sailed to San Francisco to join the Scouting Force, and for the years preceding World War II participated in Fleet Problems and maneuvers in the Pacific.

President Franklin Roosevelt came aboard on 1 July 1934 at Annapolis, Maryland, for a cruise of almost 12,000 nautical miles (14,000 mi; 22,000 km) through the Caribbean and to Portland, Oregon, by way of Hawaii.

Houston celebrated the opening of the Golden Gate Bridge at San Francisco on 28 May 1937, and carried President Roosevelt for a Fleet Review at the same city on 14 July 1938.

[6][7] Houston became flagship of the U.S. Fleet on 19 September, when Rear Admiral Claude C. Bloch brought his flag aboard, and maintained that status until 28 December, when she returned to the Scouting Force.

[5] Assigned as flagship of the Hawaiian Detachment, the cruiser arrived in Pearl Harbor after her post-overhaul shakedown on 7 December 1939, and continued in that capacity until returning to Mare Island on 17 February 1940.

On the night of the Pearl Harbor attack, Houston got underway from Panay Island with fleet units bound for Darwin, Australia, where she arrived on 28 December 1941 by way of Balikpapan and Surabaya.

ABDA suspected the presence of Japanese carriers, an imminent invasion of Timor, and a support fleet lying in wait and thus ordered the convoy back to Darwin, which it reached before noon on 18 February.

[10] Shortly after departure, Peary broke off to chase a suspected submarine, and expended so much fuel in doing so that the destroyer returned to Darwin instead of continuing with Houston.

[10] Houston thus escaped the Japanese attack on Darwin on 19 February, in which Peary, Meigs and Mauna Loa were among the ships sunk and Portmar was forced to beach.

[11][12][13] Receiving word that the major Japanese invasion force was approaching Java protected by a formidable surface unit, Admiral Doorman decided to meet and seek to destroy the main convoy.

[5] Captain Albert Rooks was killed by a bursting shell at 00:30, and as the ship came to a stop, Japanese destroyers moved in, machine-gunning the decks and men in the water.

[5] Of the 1,061 aboard, 368 survived, including 24 of the 74-man Marine Detachment, only to be captured by the Japanese, interned in prison camps, and forced to work on the infamous Burma Railway.

Of 368 Navy and Marine Corps personnel taken prisoner, 77 (21%) died in captivity from a combination of starvation, cruel treatment at the hands of Japanese soldiers, and tropical diseases.

[19][a] Houston's fate was not fully known by the world for almost nine months, and the full story of her last fight was not told until the survivors were liberated from prison camps at the end of the war.

[5] Chaplain George S. Rentz, who had surrendered his life jacket to a younger sailor after finding himself in the water, was posthumously awarded the Navy Cross.

The crew of Houston is honored alongside that of Perth at the Shrine of Remembrance in Melbourne, Australia, and in St John's Anglican Church, Fremantle.