The ship departed on a seven-night sailing from Fort Lauderdale on Saturday (26 June), with Royal Caribbean Group chair Richard Fain describing the achievement as a "momentous sailing" for the industry.
"It’s not only a huge honour to be the first ship back in the water, leading the industry in the long-awaited return to US-based cruising, it’s also an incredible achievement and testament to the tireless efforts of our shoreside team and onboard crew," he added.
"The significance of this moment is not lost on anyone on our team or the industry.
"We have longed for this day, not only because it represents a return to service and doing what we love to do most, but because we know that for many the return of cruising is a symbol of the world’s return to normalcy."
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In the UK, Celebrity Silhouette will depart Southampton on 3 July, while Celebrity will resume its operations in the Galapagos with Celebrity Flora restarting voyages on 4 July.