The freighter docked with the orbital station on February 13, bringing 2.4 tons of supplies, including oxygen, food, clothes and medical equipment for the ISS crew.
"The command for undocking was transmitted at 19:15 Moscow time [15.15 GMT], and the spacecraft separated from the Pirs docking port three minutes later," a Mission Control official said.
During its ensuing automatic flight, to last until May 18, the craft will be used as an orbital laboratory to conduct a series of geophysical experiments under the Plasma-Progress program.
It will then reenter the Earth's atmosphere before plunging into a "spaceship cemetery" in the southern Pacific.
The Progress M-66 is one of the few remaining cargo spacecraft to be equipped with analogue control systems. The next generation of Progress vehicles will be digitally controlled.