Atlantis cruised over the Florida Everglades and Lake Okeechobee before touching down on Kennedy's runway 33 at 8:48 a.m. EDT.
The spacecraft's last mission, officially known as STS-132, saw its crew conduct series of operations at the International Space Station. They dropped off a Russian mini-research module, new batteries for the station's truss and dish antenna, and other replacement parts.
The veteran crew included commander Ken Ham, pilot Tony Antonelli, and mission specialists Michael Good, Garret Reisman, Piers Sellers, and Steve Bowen.
Only two more shuttle flights now remain. The decision to cancel the shuttle program was made under the administration of former president George W. Bush, in part due to the 2003 destruction of Columbia, which exploded upon reentry into the Earth's atmosphere. All seven crewmembers were killed.
The program had previously lost a crew of seven when Challenger blew up shortly after liftoff on January 28, 1986.
President Obama has stuck with the cancellation plan, and in addition decided to kill a Bush initiative that would have seen astronauts return to the moon by 2020 in a new system comprising the Ares rocket and Orion crew capsule.
Obama's current fiscal budget proposal scraps Ares and retasks Orion as an emergency lifeboat that would be permanently docked at the ISS.
NASA engineers recently tested an escape system for Orion that's designed to jettison the capsule away from the launch pad in the event of an emergency like the one that claimed the Challenger astronauts.