The destroyer was involved in a collision with the tanker ship Alnic MC on 21 August 2017 off the coast of Singapore, which resulted in the deaths of 10 of her crew, and left another five injured.

Her maiden deployment was from 10 November 1995 to 10 May 1996 to the 5th and 7th fleets with visits to Kochi, India, Fremantle and Newcastle Australia and Suva Fiji.

[9] On 11 June 2009, a Chinese submarine reportedly collided with the towed sonar array of John S. McCain near Subic Bay, Philippines.

[12] In March 2011, in company with the aircraft carrier Ronald Reagan, the ship was deployed off northeastern Honshu, Japan, to assist with relief efforts after the 2011 Tōhoku earthquake.

[17] In June 2014, John S. McCain was sent to Subic Bay to perform in CARAT (Cooperation Afloat Readiness and Training) exercises.

[18] In August 2017, John S. McCain sailed within 6 nautical miles (7 mi; 11 km) of Mischief Reef in the South China Sea, exercising a claim to freedom of navigation.

"[19] At 5:24 am on 21 August 2017, John S. McCain was involved in a collision with the Liberian-flagged Alnic MC off the coast of Singapore and Malaysia, east of the Strait of Malacca.

[7][20][21] According to a United States Navy press release, the breach "resulted in flooding to nearby compartments, including crew berthing, machinery, and communications rooms.

[27] The U.S. Navy announced on 24 August 2017 that it had suspended search-and-rescue efforts for survivors in the open sea to focus on the recovery of the remains of the missing sailors still inside the flooded compartments of the ship.

[29] On 12 September 2017, the United States' chargé d'affaires Stephanie Syptak-Ramnath expressed thanks for Singapore's support during the SAR operations.

[38] On 4 September 2024, the US Navy relieved the captain of the USS McCain of duty because of a loss of confidence in his ability to lead after a steering issue led to a near miss in the Middle East.