The Dragon capsule pulled away from the orbiting lab with a test dummy named Ripley as its lone occupant.
It is aiming for a splashdown in the Atlantic off Florida’s coast, the final hurdle of the six-day test flight.
Its launch on Saturday and docking on Sunday went without a hitch.
Canadian station astronaut David Saint-Jacques was the first to enter the Dragon capsule when it arrived and the last to leave. He said he found the capsule “very slick” and called it business class.
Nasa astronauts have been stuck riding Russian rockets since space shuttles retired eight years ago.
Nasa is counting on SpaceX and Boeing to start launching astronauts this year.