"The space shuttle has changed the way we view the world. It has changed the way we view our universe," he said. "There was a lot of emotion today but one thing is indisputable: America is not going to stop exploring."
Twin sonic booms erupted over Florida moments before the shuttle came home to perfect summer weather with cloudless skies and hardly any wind at the Kennedy Space Center.
"Hearing the sonic booms as Atlantis came home for the last time really drove it home to me that this has been a heck of a program," said Mike Moses, space shuttle launch integration manager.
Astronauts emerged from the spacecraft and greeted NASA officials and mission managers, exchanging hugs, kisses and smiles as they admired the orbiter for a final time.
"I just want to salute this crew, welcome them home, and let them know how proud we are of them," NASA administrator Charles Bolden said.
"Children... who dream of being astronauts today won't get to fly on the space shuttle, but one day they may walk on Mars.
"I was proud to be a part of the shuttle program and will carry those cherished memories and experiences with me for the rest of my life," the former astronaut said through tears. "But I am also ready to get on with the next big challenge."
The bittersweet end to the storied shuttle career came 42 years after US astronaut Neil Armstrong became the first person to set foot on the Moon as part of the Apollo 11 mission.
The last shuttle mission, known as STS-135, was a nearly 13-day trip to restock the ISS for a year with several tons of supplies and food.
Over the course of the program, five NASA shuttles -- Atlantis, Challenger, Columbia, Discovery and Endeavour -- have comprised a fleet designed as the world's first reusable space vehicles.
Since the first shuttle space flight launched on April 12, 1981, the five shuttles have traveled more than 542 million miles (872 million kilometers), and carried 355 people from 16 different countries, NASA said.
Columbia exploded in 2003 and Challenger was destroyed in 1986 in accidents that killed a total of 14 crew members.
Those disasters left only three in the space-flying fleet, along with Enterprise, a prototype that never flew in space. The quartet will become museum pieces in the coming months.
At Kennedy Space Center, and also at mission control in Houston, employees were joyful and nostalgic.
"I saw grown men and grown women crying today, tears of joy to be sure," said Mike Leinbach, space shuttle launch director.
Critics have assailed the US space agency for lacking focus with the space shuttle gone and no next-generation human spaceflight program to immediately replace it.
The astronaut corps now numbers 60, compared to the 128 employed in 2000, and thousands of people are being laid off from Kennedy Space Center. But NASA chiefs say future missions to deep space should revive hope in the US program.
"I recognize that change is really hard, but huge growth or huge improvement comes from change," said Bill Gerstenmaier, associate administrator for space operations.
NASA is building a Multi-Purpose Crew Vehicle it hopes could send humans to an asteroid in 2025 and explore Mars by 2030, while it turns over low-orbit space travel and space station servicing to commercial ventures.
A commercial launcher and capsule built by a private corporation in partnership with NASA may be ready to tote crew members as early as 2015.
Until the private sector fills the void left by the shuttle's retirement, the world's astronauts will rely on Russian Soyuz rockets for rides to the ISS.
"Savor the moment, soak it in, and know you are the best -- the best in the world. Your work here has made America and the world a better place," said flight director Tony Ceccacci as he signed off for a final time.
"It's been an unbelievable and amazing journey."