Vessels of the squadron were primarily involved in matters relating to American commerce with China and Japan, though it participated in several conflicts over 34 years of service until becoming the Asiatic Fleet in 1902.

The objective of the operation was to ascertain the fate of the merchant ship SS General Sherman, establish trade relations, and receive an assurance from the Joseon government that shipwrecked American sailors would be safely treated should they become stranded in Korea.

On 1 June 1871, while Rear Admiral Rodgers was negotiating in Inchon, one of the Selee River forts opened fire on Palos as she traversed the Gangwha Straits.

On 20 June 1898, the Asiatic Squadron protected cruiser USS Charleston captured Guam from the Spanish without resistance, beginning the American possession of the island.

Baltimore and Petrel served at the Battle of Iloilo, in which about 1,000 Filipinos were defeated when the two warships bombarded the fort there and sent United States Marines and sailors ashore.

During a routine patrol, the collier USS Zafiro entered Subic Bay and came under fire from a shore battery protecting Olongapo.

On 23 September 1899, Charleston, Concord, the monitor USS Monterey, and Zafiro steamed into Subic Bay and destroyed the battery in the Battle of Olongapo.

Asiatic Squadron gunboats took part in the Battle of Mabitac in June 1900, where they bombarded Filipino forces while U.S. Army troops attacked their fortifications.

In November 1900, the Asiatic Squadron auxiliary cruiser USS Yosemite was heavily damaged in a typhoon while in Apra Harbor, Guam.

The gunboat USS Vicksburg assisted land forces in capturing the Filipino rebel Emilio Aguinaldo in March 1901 at Palawan Island.

Later the gunboat USS Isla de Luzon supported the operation which led to the capture of the Filipino general Vicente Lukbán on Samar in November 1901.