The experimental solar-powered aircraft, piloted by Swiss adventurer Bertrand Piccard, took off at 3:00 am (1000 GMT), live footage showed, for the latest stage of its around-the-world flight aimed at drawing attention to clean energy technologies.
"Goodbye Phoenix, thank you for your warm and friendly welcome," Piccard tweeted from the cockpit.
The flight to the city of Tulsa is expected to take 17 and a half hours.
The plane is set to make one or two more stops in the United States before finally landing in New York City, in the latest leg of a journey that kicked off in Abu Dhabi on March 9, 2015.
"The objective is to reach New York as soon as possible!" the Solar Impulse 2 team said in a statement Wednesday, although it is not clear when the plane might reach there.
The aircraft was grounded in July last year when its batteries suffered problems halfway through its 21,700-mile (35,000-kilometer) circumnavigation.
The crew took several months to repair the damage from high tropical temperatures during the flight's final Pacific stage, a 4,000-mile (6,437-kilometer) flight between Nagoya, Japan and Hawaii.
The plane was flown on that stage by Piccard's teammate Andre Borschberg, whose 118-hour journey smashed the previous record of 76 hours and 45 minutes set by US adventurer Steve Fossett in 2006.
The Solar Impulse 2's wings, wider than those of a Boeing 747, contain 17,000 solar cells that power the aircraft's propellers and charge batteries.
At night, the plane runs on stored energy.
The typical flight speed is around 30 miles (45 kilometers) an hour, which can increase to double that when exposed to full sunlight.
After crossing the United States, the pilots are set to make a trans-Atlantic flight to Europe, from where they plan to make their way back to their point of departure in Abu Dhabi.
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