Thousands of people gathered to watch in the port of Saint-Nazaire as the 70m (230ft) high vessel was guided out to sea by six tugs on Thursday.
The â‚¬1bn (Â£783m; $1.1bn) ship is being built for the Royal Caribbean International (RCI) cruise company.
The 120,000-tonne vessel is expected to be delivered to the US-based firm in two months.
The trial will continue until Sunday.
The 16-deck Harmony of the Seas is 362m long - 50m longer than the Eiffel Tower is high.
After completion, it will be able to accommodate more than 6,000 passengers.
About 2,000 crew members will cater for their needs.
Harmony of the Seas, the world's largest cruise ship, has begun its first sea trial in western France.