Bob Behnken and Doug Hurley left the International Space Station in the early hours of Sunday for the final and most important part of their SpaceX test flight on the Crew Dragon.
They are aiming to land their capsule by parachute in the Gulf of Mexico near Pensacola in west Florida, the first splashdown for astronauts in 45 years.
NASA has forecast favourable weather for their expected arrival on Sunday at about 7.48pm (UK time), despite the approach of Hurricane Isaias, which weakened to a tropical storm on Saturday, but was expected to regain hurricane strength when it hit the state.
The centre of the storm was due to approach Florida's southeast coast on Sunday morning before travelling up the east coast during the day.
Flight controllers will be watching the storm closely after it caused flooding and landslides on Thursday in the Dominican Republic and Puerto Rico.
A man died in the Dominican Republic and a woman's body was recovered from floodwaters in Puerto Rico on Saturday, where the National Guard had to rescue at least 35 people.
Mr Hurley and Mr Behnken launched from the Kennedy Space Center on 30 May, making Elon Musk's SpaceX the first private company to send people into orbit.
It was also NASA's first crewed mission from home soil in nine years.
Space station commander Chris Cassidy, who will remain on board with two Russians until October, said: "We're a little sad to see them go."
Mr Cassidy rang the ship's bell as Dragon pulled away 267 miles above South Africa and, just minutes later, the capsule appeared as just a pair of flashing lights.
Mr Hurley had radioed back to the space station to say: "It's been a great two months, and we appreciate all you've done as a crew to help us prove out Dragon on its maiden flight."
Mr Cassidy replied: "Safe travels and have a successful landing."
The next SpaceX flight is at the end of September, while rival Boeing is expected to launch its first crew next year.
https://news.sky.com/story/astronauts-head-towards-splashdown-off-florida-coast-as-powerful-storm-approaches-state-12040779