Donald Trump has ordered NASA to plan a new manned mission to the Moon for the "first time since 1972 for long-time exploration".
The US president signed a policy directive on Monday instructing the National Aeronautics and Space Administration to refocus America's space programme on "human exploration and discovery".
The move, Mr Trump said, "marks an important step in returning American astronauts to the moon".
He added: "This time we will not only plant our flag and leave our footprint, but we will establish a foundation for an eventual mission to Mars, and perhaps someday, to many worlds beyond."
Past presidents, including George HW Bush and George W Bush, also proposed returning to the moon and launching missions to Mars but were constrained by budget issues.
Mr Trump was joined at the White House by several current and former astronauts, including Buzz Aldrin, the second man to walk on the moon, and former US Senator and Apollo 17 astronaut Harrison "Jack" Schmitt, the second-last person on the moon.
He added: "Today we pledge that he will not be the last, and I suspect we'll be finding other places to land in addition to the moon."
No human has been on the moon since Apollo 17 in December 1972. Only 12 men have set foot on the moon, all have been Americans.
Under the directive, the government is also expected to work closely with other nations and private industry.