St. Louis was specially outfitted with heavy drag lines in order to destroy undersea cable communications in the West Indies and to the mainland of South America.

When Admiral Pascual Cervera's fleet sailed into Santiago Harbor, the Spanish warships found themselves cut off from direct communications with Spain.

She joined in the bombardment of fortifications at Caimanera in Guantanamo Bay on 3 June; captured a Spanish merchant ship on the 10th; intercepted two British ships bound for Cuba - the Twickenham on 10 June and Wary on 1 July; and was present at the Battle of Santiago de Cuba on 3 July when the Spanish Fleet was destroyed while trying to force its way to sea.

St. Louis received many prisoners of war, including Admiral Cervera, for internment in the United States and landed them at Portsmouth, N.H., on 11 July.

[1] On 17 March 1917, she was provided with an armed guard of 26 sailors and equipped with three 6-inch guns to defend against enemy attack on her New York-to-Liverpool service route.

On 30 May, while proceeding up the Irish Sea and skirting the coast of England, she responded rapidly to the orders, "Hard Starboard," at the sighting of a periscope, and succeeded in dodging a torpedo while apparently striking the submarine which fired it.

From then until 19 August of that year, she made six voyages from New York to Liverpool or to Brest, France, to return American soldiers from the Great War.