An Emirates Airlines flight EK 232 carrying the prime minister and members of her entourage took off from the Washington’s Dulles International Airport at 10.55 am local time (8.55 pm BST).
The premier is scheduled to reach Dhaka via Dubai Friday afternoon.
Bangladesh Ambassador in the USA M Ziauddin and Bangladesh's Permanent Representative to the United Nations Masud Bin Momen and senior officials of Bangladesh Embassy saw the prime minister off at the airport.
A large number of expatriate nationals were present at the airport to bid farewell to the prime minister.
The prime minister left Dhaka on September 14 for a two-nation tour in North America.
In the first leg, she paid a four-day visit to Canada from Sept 15-18 to attend the Fifth Replenishment Conference of the Global Fund (GF) on deadly diseases at the invitation of her Canadian counterpart Justin Trudeau.
In the second leg, she went to New York to join the 71st session of the United Nations General Assembly (UNGA).
During her stay in New York, the premier also held bilateral talks with world leaders and took part in the discourses on global issues.