The Dragon vehicle, dubbed Endeavour, undocked from the space station as planned shortly after 2 p.m. EST (1900 GMT) in a process carried live by a NASA webcast, with video showing the astronauts strapped into the cabin wearing their helmeted white flight suits.
Operating autonomously, the spacecraft began its departure with a 90-minute fly-around of the space station as the crew snapped a series of survey photographs of the orbiting outpost, circling the globe some 250 miles (400 km) high.
If all goes smoothly, Endeavour was scheduled to parachute into the Gulf of Mexico off the Florida coast at about 10:30 p.m. EST on Monday (0330 GMT Tuesday), following a total return flight time of eight hours, including a fiery re-entry through Earth's atmosphere.
In a final sequence of maneuvers before leaving Earth orbit, the crew-cabin section of Space Dragon is designed to jettison the vehicle's lower "auxiliary trunk" to expose the capsule's protective heat shield.
Propelled by one last ignition of its rocket thrusters for a "de-orbit burn," the capsule was expected to re-enter the atmosphere at about 17,500 miles per hour (28,163 kph) for its free-fall descent toward the ocean below, during which crew communications will be lost for several minutes.
Frictional heat generated as the capsule plunges through the atmosphere typically sends temperatures surrounding the outside of the vehicle soaring to 3,500 degrees F (1,927 degrees C).
The capsule and crew are to be picked up at sea by a special recovery team standing by in the Gulf.
The crew consists of two NASA astronauts - mission commander Shane Kimbrough, 54, and pilot Megan McArthur, 50 - along with Japanese astronaut Akihiko Hoshide, 52, and fellow mission specialist Thomas Pesquet, 43, a French engineer from the European Space Agency.
They were lofted to orbit atop a SpaceX Falcon 9 rocket that lifted off on April 23 from the Kennedy Space Center in Florida.
It was the third crew launched into orbit under NASA's fledgling public-private partnership with SpaceX, the rocket company formed in 2002 by billionaire entrepreneur Elon Musk, who also founded electric car maker Tesla Inc.
The returning team was designated "Crew 2" because it marks the second "operational" space station team that NASA has launched aboard a SpaceX capsule since resuming human spaceflights from American soil last year, after a nine-year hiatus at the end of the US space shuttle program in 2011.
The replacement team, "Crew 3," was originally slated to fly to the space station at the end of October, but that launch has been delayed by weather problems and an unspecified medical issue involving one of the four crew members.
One irregularity confronting the returning Crew 2 was a plumbing leak aboard the capsule that put the spacecraft's toilet out of order, requiring the astronauts to relieve themselves in their spacesuit undergarments if nature called during the flight home, according to NASA.
