P&O’s Pacific Explorer departed at 4pm from the White Bay Cruise Terminal in Balmain for a four-night round trip to Brisbane.
Thousands of cruise fans are on board the mammoth vessel, which has set sail under the Harbour Bridge on its way out to the ocean with great fanfare.
The 999-cabin ship, which arrived back in Sydney last month, will become the first to berth at the Brisbane International Cruise Terminal.
It boasts 18 restaurants, seven bars and clubs and the first bowling green on an Aussie ship.
Cruises were banned in March 2020 when COVID-19 lockdowns began, following an outbreak on the Ruby Princess.
The ban was lifted earlier this year, but the mammoth vessels have only just started to arrive back.
President of Carnival Australia and P&O Cruises Australia Marguerite Fitzgerald said it would be an “emotional moment” when the ship sets sail.
The voyage is being welcomed by the $5 billion industry which supports 18,000 Aussie jobs.
A total of 1.35 million Aussies took a cruise in 2018.
Peak season is between December and March.
Prior to the pandemic, cruising accounted for more than $1 billion annually in economic activity in Queensland, with regional destinations from Moreton Island to Cairns benefiting.
More cruise ships are due back in Australia in coming months.
In June, Princess Cruises will home port Coral Princess in Brisbane, marking a ten-year Princess relationship with the city.
In 2023, Carnival Cruise Line will also home port a ship in the city.
Cunard’s lavish Queen Elizabeth will call at Airlie Beach, Cairns and Port Douglas in November.
Sister ship Queen Victoria will call at Cairns in March 2023, with flagship Queen Mary 2 visiting Airlie Beach and Brisbane the same month.
The nation is one of the last in the world to allow cruises again.
Cruisers must be fully vaccinated and take a rapid test to board.