Aside from a cruise to Hawaii and Samoa in the fall of 1909, the cruiser operated along the west coast, sharpening her readiness through training exercises and drills, until December 1911, when she sailed for Honolulu, and in March 1912 continued westward for duty on the Asiatic Station.

After this service representing American power and prestige in the Far East, she returned home in August 1912, and was ordered to Corinto, Nicaragua, then embroiled in internal political disturbance.

Here she protected American lives and property, then resumed her operations along the west coast; she cruised off California, and kept a watchful eye on Mexico, at that time also suffering political disturbance.

She served as flagship for Commander-in-Chief, Pacific Fleet, intermittently until a boiler explosion put her in Mare Island Navy Yard in reduced commission through the summer of 1915.

The boiler explosion occurred in January 1915 and the actions of Ensign Robert Cary and Fireman Second Class Telesforo Trinidad during the event earned them both the Medal of Honor.

Based in Tompkinsville, New York, and Halifax, Nova Scotia, she operated in the weather-torn, submarine-infested North Atlantic safely convoying all of her charges to the ocean escort.

In his report to a Board of Inquiry on the cruiser's loss, Christy stated that all lookouts, gun watches, and fire control parties were at their appointed stations and on full alert, and that all necessary orders to safeguard the watertight integrity of the ship in dangerous waters had been given and were being carried out.

Captain Christy assumed that the ship had been torpedoed and immediately sounded submarine defense quarters and ordered all guns to open fire on anything resembling a periscope.

Aircraft of the First Yale Unit, based at Bay Shore, Long Island, attacked what they thought was a submerged submarine lying on the seabed in around 100 ft (30 m) and dropped several bombs; it turned out to be San Diego.

[13] It was subsequently reported that experienced merchant officers believed that a mine was the probable cause, due to the violence of the explosion and the rapidity with which the ship sank.

[21] In December 2018, at the annual meeting of the American Geophysical Union, Alexis Catsambis, an underwater archaeologist with the Navy, stated "We believe that U-156 sunk San Diego".

"Torpedoes of the time carried more explosives than mines – and would have shown more immediate damage," stated University of Delaware marine scientist Arthur Trembanis, who took part in the latest wreck study.