The men are the first prisoners from the US base in Cuba to be sent to South America.
All six had been detained for suspected ties to al-Qaeda but were never charged. A Pentagon statement on Sunday identified the men as four Syrians, a Tunisian and a Palestinian.
Uruguayan President Jose Mujica agreed to accept the men earlier this year as refugees but the transfer was delayed until Sunday, after the country's recent presidential election, Al Jazeera reported.
Their release brings the total number of prisoners at Guantanamo to 136 - the lowest number since the first month the prison opened in January 2002.