The SpaceX Dragon Capsule carrying Doug Hurley and Bob Behnken came down in the Gulf of Mexico just south of Pensacola on Florida's Gulf coast.
A recovery vessel moved in to pick up the vehicle and extricate the men.
The touchdown marks the first crewed US water landing since the final outing of an Apollo command module 45 years ago.
Hurley's and Behnken's capsule touched the water at about 14:48 EDT (19:48 BST; 18:48 GMT).
Private boats which came close to the Dragon were asked to leave amid concern over hazardous chemicals on the capsule.
Nasa administrator Jim Bridenstine said the presence of the boats "was not what we were anticipating".
"What is not common is having passersby approach the vehicle close range with nitrogen tetroxide in the atmosphere, that's not something that is good," he said. "And we need to make sure that we're warning people not to get close to the spacecraft in the future."
Photos of the boats were shared on social media.