Discovery glided down on Monday through an overcast sky onto the Kennedy Space Centre runway at 9.14am (1314 GMT).
The shuttle’s re-entry follows a 13-day mission to the International Space Station (ISS).
Mission Control waited until almost the last minute before notifying the astronauts that the weather was good enough to come home.
Commander Steven Lindsey and co-pilot Mark Kelly then began the hour-long descent.
The shuttle’s flight is only the second mission since 2003 when the Columbia exploded on re-entry, killing all its crew.
On landing Lindsey said: “It was a great mission, a really great mission.”
Scott Kelly, astronaut and the identical twin brother of Mark Kelly said: “It’s exciting to see the shuttle back, we’re back on track with maybe flying the shuttle regularly here starting again in August.”
The Discovery had launched with seven astronauts, but departed the space station on Saturday with six.
Thomas Reiter, a German astronaut, was left behind for a six-month visit, joining two other men there and increasing the station’s crew to three.
The Discovery mission conducted three spacewalks, one of them to test shuttle patching techniques, and used a 30m inspection crane to check the shuttle’s thermal armour for any damage from launch or orbital debris.
The mission also undertook vital repairs in order to resume building work on the ISS.
After climbing out of the shuttle Lindsey said: “We’re ready to go assemble the station and we’re ready to start flying shuttles on a more regular basis.”