A boat was ferrying the spacecraft to a port near Los Angeles, where NASA said the haul of 1.5 tonnes of experiment results and other materials will be removed and returned to the space agency by late tomorrow for scientists to pick apart.
Dragon also carried crew supplies, hardware and computer resources.
The investigations in the cargo could help develop more efficient solar cells and semiconductor-based electronics, as well as grow plants better suited for space and improve sustainable agriculture, according to NASA.
Dragon, which spent a month at the space station, will later travel back for processing to SpaceX's test facility in McGregor, Texas.
Astronauts at the ISS had manipulated the orbiting lab's robotic arm to detach Dragon on time, at 1357 GMT, in what NASA called a "very clean release."
The capsule splashed down five-and-a-half-hours later, at 1939 GMT, near the Mexican coast, slowed by three enormous parachutes.
The SpaceX vessel is the only spacecraft currently capable of returning from the ISS with cargo. Its last mission to the space station was in April.
The lab mice were the first live mammals to hitch a ride aboard a commercial cargo ship, and they are enclosed in a NASA-made research cage for studying the effects of weightlessness on their bodies.
The 3D printer is the first of its kind to demonstrate how the technology can be used in space, even without gravity to assist the process.
The Dragon return kicks off a week of heavy traffic to and from the orbiting science lab.
And on Wednesday, the Russian cargo ship Progress is set to take off for the ISS, replacing a sister vessel due to break away from the orbiting station and return to Earth tomorrow.
