Undocked from the Harmon node of the ISS, the Dragon fired its engines to send it to a splashdown in the Pacific Ocean at 12:34 EDT, the space agency reported Tuesday.
SpaceX engineers, technicians and divers will recover the vehicle off the coast of Baja California to bring it back to shore in a journey expected to take about 30 hours, NASA said.
Dragon's return was delayed for one day because of bad weather in the target splashdown site.
The Dragon spacecraft launched on a SpaceX Falcon 9 rocket from Cape Canaveral Air Force Station in Florida to deliver about 1,200 pounds of science experiments and hardware to the ISS.
It was the second commercial resupply mission to the station for SpaceX; a third is scheduled for late September, NASA said.