Atlantis spent eight days docked to the ISS
The shuttle, with its five astronauts, touched down on a floodlit runway at the Kennedy Space Center at 0338 GMT, almost 24 hours after an earlier scheduled landing was delayed by bad weather.
Mission Control told commander Steven Lindsey and his crew: "It looked like an outstanding landing after an outstanding mission. Well done."
Commander Lindsey replied: "It's great to be home."
During its mission, the crew carried out three spacewalks to install a new $164m airlock on the space station.
Before this, it had only been possible to carry out spacewalks by leaving the station through airlocks of a docked space shuttle.
Now, astronauts living on the space station will be able to work outside the craft even when a shuttle is not there.
New 'front door'
Shuttle programme manager Ron Dittemore said the seven space station construction flights in less than a year had given rise to "a small city in the sky".
"It was just a tremendous feat for all those involved," he said.
"It was a great mission and we accomplished just what we intended to do."
US astronauts Michael Gernhardt and James Reilly made use of the airlock for the first time on Saturday as they floated out into space to hang a high-pressure gas tank on the side of the door.
A total of three spacewalks were required to install the new "front door" or Joint Airlock Module (JAM).
The JAM, which measures four metres (13 feet) across and 5.5 metres (18 feet) in length, was anchored to the ISS with the help of the station's advanced Canadarm2, which was added to the platform in April.
Two Americans and a Russian have been aboard the station since March.
They plan to return to Earth on the next flight, due to be made by the shuttle Discovery next month.