Solar Impulse took off from Nagoya Airfield in Japan at 18:03 GMT and is scheduled to land in Hawaii in approximately 120 hours.
The team has spent nearly two months waiting for a clear weather window to cross the Pacific.
The first attempt to fly over the ocean was cut short after a change in the forecast forced an unscheduled landing.
And another attempt to take off last Tuesday was cancelled at the last moment because of concerns about the conditions.
This time, the team will not be widely publicising the take-off until the plane is several hours into its flight, as it may need to turn back if the forecast changes.
However, if the pilot succeeds, it will be the longest-duration solo flight in aviation history, as well as the furthest distance flown by a craft that is powered only by the Sun.
The Pacific crossing is the eighth leg of Solar Impulse`s journey around the world.
But this stage has proven to be the most difficult, and has been hit by weeks of delays.