Astronauts set the world's first commercial supply ship loose after a five-day visit, releasing the vessel with the space station's robot arm. The Dragon slowly backed away from the 250-mile-high (400-kilometer-high) outpost, on track for a midday return to Earth, six hours later.
The targeted splashdown zone is 560 miles (900 kilometers) west of Baja California, Mexico.
"Dragon smoothly undocked, moved out, released and on its way home," Dutch astronaut Andre Kuipers reported via Twitter.
The US space agency, NASA, has turned to American private business to take over cargo runs and, eventually, astronaut ferry flights after its space shuttles were retired last year. Several companies are in the running for the human missions, with SpaceX in the lead.
President Barack Obama wants NASA free of orbital deliveries so it can work on getting astronauts to asteroids and Mars.
NASA's Mission Control quickly radioed praise to the six-man space station crew Thursday: "Great work, guys." Within minutes, the capsule was outside the NASA-controlled safety zone around the space station and under the complete jurisdiction of the SpaceX team in California.
Last week, SpaceX became the first private company to send a cargo ship to the International Space Station. And Thursday, it was on the verge of becoming the only supplier to return major items.
The unmanned Dragon capsule is returning more than a half-ton of old space station equipment and some science samples. Because it is a test flight, NASA did not want to load it with anything valuable.
The capsule was set to parachute down in the style of NASA's old Mercury, Gemini and Apollo spacecraft. A Dragon has returned from orbit once before, on a solo mission in December 2010.
Russia's Soyuz spacecraft for carrying crews also parachutes down, but on land, deep inside Kazakhstan. All of the government-provided cargo vessels of Russia, Europe and Japan, meanwhile, burn up on descent.
SpaceX's billionaire founder, Elon Musk of PayPal fame, expects to have astronauts riding his Dragons in three or four years.
Assuming Thursday's entry goes well, the next Dragon supply mission will be in September.