Cheyenne was the first ship to launch Tomahawk missiles in Operation Iraqi Freedom[3] under the command of CDR Charles Doty.

Cheyenne would go on to successfully launch her entire complement of Tomahawks, earning a "clean sweep" for combat actions in the final three months of a nine-month deployment.

Between 25 and 27 March 2006, a series of anti-submarine warfare exercises were held in Hawaiian waters that included USS Cheyenne; Carrier Strike Group Nine, the nuclear-powered attack submarines Seawolf, Greeneville, Tucson, and Pasadena, as well as land-based P-3 Orion aircraft from patrol squadrons VP-4, VP-9, and VP-47.

In June 2021, Cheyenne shifted her homeport from Pearl Harbor to Groton, CT, joining Submarine Squadron (SUBRON) 12.

[7] Cheyenne arrived in November 2021 at Portsmouth Naval Shipyard in Kittery, Maine to begin a service-life extension program (SLEP) expected to take 30 months and cost $315 million.