Following her christening, Millennium sailed her maiden voyage on 1 July 2000 from Amsterdam to Baltic ports. Following an inaugural Europe season, she debuted in North America in New York in November 2000 before re-positioning in December to Port Everglades in Fort Lauderdale, Florida to sail cruises in the Caribbean through the winter. She sailed in the Mediterranean the following summer. Since 2001, the ship has sailed extensively throughout Europe, Australasia, and the Caribbean.

In May 2011, a female passenger in her sixties was declared missing when she failed to disembark at a port call in San Diego. Security cameras on the ship showed that she had jumped off the ship into the waters between Cabo San Lucas and San Diego.

In December 2012, the ship debuted in Asia after arriving at her homeport of Singapore, where the ship has been primarily deployed through the winter; in the summer, she has primarily sailed in Alaska.

Because of the COVID-19 pandemic, in February 2020, Celebrity cancelled all Asia cruises on Celebrity Millennium and re-deployed her to Los Angeles to sail complimentary cruises in March and April 2020 for first responders and military personnel. However, all sailings were cancelled after the company halted operations on 13 March 2020. The ship was berthed or anchored offshore near San Diego throughout much of the pandemic; after months of difficulty repatriating crew members, up to 480 crew members still remained on board the ship in May 2020.

In summer 2021, Celebrity Millennium joined Celebrity Edge in becoming the second ship in its fleet to re-start North American Operations, offering few sailings out of St. Maarten prior to being repositioned to Seattle were in July 23 she became the 2nd ship worldwide to resume Alaska sailings.