The man was aboard the Quantum of the Seas ship that departed Brisbane for the Hawaiian islands on April 12.
Cruise operator Royal Caribbean said the guest had gone overboard on the trans-Pacific leg of the journey.
"The ship's crew immediately launched a search and rescue operation and is working closely with local authorities," a spokeswoman said in a statement.
The incident reportedly happened shortly before midnight on Tuesday, local time, or Wednesday night, AEST.
Cruise ship passenger Georgina Thompson, who is currently on board the vessel, told Channel 9's Today show she heard repeated calls of a man's name over the PA system.
"There were lights … shining on the ocean and also there were a couple of boats out there in the water," she said.
"The light started searching along the outside of the ship.
"You just knew that something was wrong. My husband thought we might have hit something."
Guests had earlier commemorated Anzac Day with a Dawn Service on board.
The US Coast Guard is conducting an aerial search for the man.
The ship is scheduled to arrive in Honolulu on Friday.
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