Nieuw Statendam has become the fifth Holland America Line ship to re-enter service since the pandemic forced a suspension of all cruises last year.
The ship resumed sailing from Fort Lauderdale in Florida on a seven-day western Caribbean itinerary.
The cruises, ranging from seven to 11 days in duration, will run until April 2022, including calls at private island Half Moon Cay in the Bahamas.
The vessel joins new-build Rotterdam, Koningsdam, Eurodam and Nieuw Amsterdam in returning to service.
HAL president Gus Antorcha said: “Today is another milestone in our return to service, with Nieuw Statendam starting operation just in time for Thanksgiving, and we have a lot to be thankful for this year that we’re getting back in the water.”