The flight carrying Martin Salia left the airport at Sierra Leone's capital Freetown at 2:30 am (GMT), Brima Kargbo, the country's chief medical officer, told AFP.
Salia had been treating Ebola patients at Freetown's Connaught Hospital, he said.
The medical evacuation is being facilitated by the US government at the request of Salia's wife, an American citizen who agreed to reimburse all expenses, State Department spokeswoman Jen Psaki said in a statement.
The patient was "critically ill," according to a statement from the US hospital where he will be treated, citing reports from health workers in Sierra Leone.
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His exact condition would be evaluated when he arrived, said the Nebraska Medical Center in Omaha, but it said Salia was "possibly sicker than the first patients successfully treated in the United States."
The hospital, one of a handful equipped to handle Ebola cases in the United States said it was expecting Salia to arrive at 2:00 pm (2000 GMT).
"We immediately started preparing the unit and notifying staff members of this possibility," Phil Smith, bio-containment unit medical director, said in the statement.
"We've obviously been through this a couple of times before so we know what to expect."
CNN had reported that Salia has several children.
There are currently no cases of Ebola in the United States, where nine people have been treated for the killer virus. Only one -- Liberian-born Thomas Eric Duncan -- has died from the disease on US soil.
Despite some hopeful signs -- Liberia has lifted its state of emergency and the DR Congo announced the end of its own, unrelated, outbreak of Ebola -- the recent deaths of three people in Mali have fueled fears of a new African hotspot.