Among the inmates transferred was Syrian prisoner Jihad Diyab, 43, who had staged a hunger strike and requested a US court to order prison officials to stop force-feeding him.
The six men received an "approved for transfer" from US authorities and left the military base on a US Air Force plane at 12:00 am (1030 IST) today, Pentagon spokesman Myles Caggins told AFP.
There are still 136 prisoners at Guantanamo, most of whom are detained without charge or facing trial, after 66 detainees were approved to be released by the successive governments of George W. Bush and Barack Obama.
"We are very grateful to Uruguay for this important humanitarian action, and to President (Jose) Mujica for his strong leadership in providing a home for individuals who cannot return to their own countries," special envoy for Guantanamo closure Cliff Sloan told AFP.
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"The support we are receiving from our friends and allies is critical to achieving our shared goal of closing Guantanamo, and this transfer is a major milestone in our efforts to close the facility."
Uruguay's leftist President Jose Mujica had announced in March that the South American country would take in the inmates on humanitarian grounds in an effort to help US President Barack Obama fulfill his long-delayed promise to close the military prison in Cuba.
By the time Washington was ready, Uruguay was in the midst of an election campaign to choose Mujica's successor, making the issue a political hot potato.
Diyab is one of several prisoners who have staged hunger strikes at Guantanamo arguing that they are being held in legal limbo.
Last year, Guantanamo prisoners staged the largest protest in the prison's history - involving two thirds of all detainees at its peak and spanning six months.