US Airways began its final flight on Friday at 10:36 a.m.
The journey is named Flight 1939, a reference to the airline's founding year.
The flight departed from Philadelphia International Airport headed for San Francisco.
It will make scheduled stops in Charlotte, Phoenix and San Francisco before returning as a red-eye flight back to Philadelphia on Saturday.
All future flights will fly under the American Airlines banner as a part of a merger deal announced in 2013.
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