The Carnival Panorama became the first cruise ship to depart from California in more than a year.
The ship, which is based in Long Beach, departed Saturday to the Mexican Riviera.
The cruise industry is massive for the area.
"We get over 600,000 passengers that come into Queen Mary Island, there at the Carnival Cruise terminal, and they visit our attractions and amenities and they stay in our hotels, so the impacts of not having tourists means we don't necessarily have jobs," John Keisler, Long Beach economic development director, told KABC.
There had been a 17-month pause on cruises in the region due to the coronavirus pandemic.
Carnival said the ship will repeat its itinerary every Saturday through December.