The aircraft, with Swiss pilot Andre Borschberg at the controls, took off from Lehigh Valley Airport shortly before midnight, a live video feed showed.
Solar Impulse 2 leaves Arizona on record-breaking flight
The light, slow-moving aircraft was expected to fly over the Statue of Liberty three hours later and across the Manhattan skyline before landing at New York's Kennedy Airport at about 4:00 am (0800 GMT) Saturday.
It is the 14th leg of an east-west journey that began March 9, 2015 in Abu Dhabi, and has taken the aircraft across Asia and the Pacific to the United States.
From New York they will attempt to cross the Atlantic to Europe and on to the Middle East.
Borschberg has alternated with fellow Swiss pilot Bertrand Piccard, a doctor who made the first non-stop balloon flight around the world in 1999.
Solar Impulse 2 completes Phoenix-San Francisco leg of round-the-world flight
Their goal is to be the first to circumnavigate the Earth with the sun as the aircraft's only source of power.
The single-seat aircraft, which has the wingspan of a Boeing 747, is clad in thousands of solar cells.
It travels at a mere 30 miles (48 kilometers) per hour.
About an hour into the latest flight, it was skimming over Pennsylvania at an altitude of less than 3,000 feet (900 meters).
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