This warship was named for the town of Harpers Ferry, West Virginia, which, because of the U.S. arsenal there, was an important location during the Civil War.

Harpers Ferry was previously stationed at the American Naval Base in Sasebo, Nagasaki, Japan before she was relieved in 2011 by USS Germantown.

Following the Cyclone Nargis disaster in Burma in 2008, and during the following "Operation Caring Response" humanitarian aid mission to Burma, Harpers Ferry steamed in Burmese waters from 13 May to 5 June, waiting for the Burmese junta government to allow American aid to be taken to its citizens.

During this operation, she was a part of USS Essex's expeditionary strike group, which also included Juneau and the guided missile destroyer Mustin,[1] However, in early June, with permission to enter Burmese airspace and land areas still not forthcoming from the Burmese government, it was decided to withdraw this aid mission and to return this Naval Task Group back to its previously-scheduled operations.

[2] In October 2009, Harpers Ferry participated in humanitarian rescue operations in the Pangasinan province, of the Philippines, following the impact of Typhoon Parma (Pepeng) that caused serious flooding.