The plane, which runs on four electric propellers powered by 12,000 solar cells mounted on the plane's 63 meter wingspan, lifted off in the dark from Lambert-St. Louis International Airport at 0902 GMT.
At the controls was Swiss pilot Andre Borschberg, who is taking turns with compatriot Bertrand Piccard on different legs of the flight across the United States.
The Solar Impulse takeoff was broadcast live on the organizer's website, live.solarimpulse.com.
The Solar Impulse can fly at night by reaching a high elevation of 27,000 feet (8,230 meters) and then gently gliding downward, using almost no power until the sun comes up to begin recharging the solar cells.
However Borschberg will be flying lower than usual Friday "because the winds are much too strong at high altitudes," said flight director Raymond Clerc just ahead of the flight.The flight is expected to last 17 hours, and the giant plane is expected to arrive at the Cincinnati Municipal Lunken Aiport in Ohio at 9 pm (0100 GMT).
Strong cross winds and heavy air traffic are expected to make flying challenging. The difficult weather thwarted plans for a direct flight from St. Louis to Washington DC.
The first-ever manned airplane that can fly by day or night on solar power alone landed in the dark at a major southwestern US airport, a live feed from the organizer's website showed early Saturday.
Solar Impulse, piloted by Swiss adventurer Bertrand Piccard, touched down at Phoenix's Sky Harbor International Airport at 0730 GMT after departing from California some 18 hours earlier on the first leg of cross-country journey.
Voice of Russia, AFP