The orbiter touched down at the Kennedy Space Center in Florida at 1314 GMT.
Mission control had raised concerns about weather conditions, but gave the go-ahead shortly before the ship began its hour-long descent.
Nasa hopes the mission's success has drawn a line under doubts over the shuttle programme's safety.
"Welcome back Discovery and congratulations on a great mission," mission control told shuttle commander Steven Lindsey, as the orbiter came to a halt on the runway after deploying its parachute.
"It was a great mission. A really great mission," Lindsey replied.
Discovery was cleared for re-entry over the weekend when inspections revealed no signs of damage to the craft.
The orbiter's flight was only the second shuttle mission since the Columbia broke up on re-entry in 2003 killing everyone on board and grounding the rest of the shuttle fleet.
Crew members were woken early on Monday to begin preparations for re-entry, one of the riskiest phases of a shuttle mission.
DISCOVERY SHUTTLE FLIGHT
Mission known as STS-121
Discovery's 32nd flight
18th orbiter flight to ISS
Landing: 0914 EDT (1314 GMT)
Landing location: Kennedy Space Center, Florida
Returning crew: Lindsey, Kelly, Fossum, Nowak, Wilson, Sellers
There had been some worry over a bank of rain clouds in northern Florida which were expected to head towards the landing site.
Once the go-ahead was given, Steven Lindsey and co-pilot Mark Kelly started the spacecraft's plunge out of orbit.
The shuttle reached a velocity of nearly 25 times the speed of sound as it hurtled through the atmosphere, generating huge amounts of heat.
No problems were reported with the ship's heat shield, and the shuttle touched down on schedule under overcast skies.
The orbiter has returned a man lighter than at take-off, having left German astronaut Thomas Reiter on board the International Space Station (ISS) for six months.
After landing, Lindsey said he and the crew had accomplished both their major objectives - completing the post-Columbia testing of the shuttle and its redesigned fuel tank, and preparing the way for Nasa to restart building work on the ISS.
The work was halted after the Columbia disaster.
The crew posed for photographs after clambering out of the shuttle
"We're ready to go assemble station," Lindsey said, "and we're ready to start flying shuttles on a more regular basis."
Nasa chiefs were delighted with the landing, and declared the flight "enormously successful".
"This is as good a mission as we've ever flown but we're not going to get over-confident," Nasa administrator Michael Griffin said.
Accident investigators said the Columbia disaster had been caused by insulating foam falling from the vehicle's external fuel tank during launch, striking the orbiter's wing and damaging the heat shield needed to protect it during re-entry.
Discovery's heat shield was examined in detail just after launch and just before re-entry. Astronauts used a laser and camera system to check over the ship's nose and belly.
The final inspection was geared in particular to look for micrometeoroid impacts that could have damaged the shuttle during its stint in space.
The Discovery mission undertook three spacewalks, including doing repairs on the ISS that were vital to resuming building work on the platform.
Before the space shuttle fleet is retired in 2010, Nasa hopes to carry out many more missions, with the goal of completing work on the ISS.
Its shuttle programme will continue next month, when the space shuttle Atlantis is scheduled to blast off.
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