"The release has been confirmed, right on time at 6:04 am Central Time (1104 GMT)," a NASA commentator said as the US space agency broadcast images of the white capsule floating away from the space station's robotic arm.
The Dragon is the only supply ship that is capable of returning to Earth intact, and is carrying some 3,100 pounds (1,400 kilograms) of cargo back from the orbiting outpost.
Splashdown in the Pacific Ocean is expected at 1642 GMT.
The ISS is staffed with half a dozen global astronauts who typically live there for about six months at a time.
Two men, American astronaut Scott Kelly and Russian cosmonaut Mikhail Kornienko, are spending one year at the lab to test the limits of the human body and mind in preparation for longer deep space missions in the future. They will depart next March.
