He is the only scientist to have walked on the Moon, and he and Eugene Cernan were the last astronauts on the Moon, flying in Apollo 17 in December 1972. They remained on the lunar surface for three days and took three excursions in the lunar roving vehicle. The 22 hours and 6 minutes they spent in extravehicular activities on the lunar surface was a record, as was their retrieval of 115 kg of lunar soil and rocks. Schmitt discovered orange glass spherules in the lunar soil.

Schmitt was selected for NASA's first group of scientist-astronauts in 1965. After his one flight, Schmitt left the programme in 1975. He served as a senator from 1976 to 1983 and has stayed active in lunar research. In 2006, Schmidtt authored a book titled Return to the Moon: Exploration, Enterprise, and Energy in the Human Settlement of Space.