With a thunderous roar that reverberated far beyond the launchpad, the enormous orange-and-white rocket carried three Americans and one Canadian away from Florida's Kennedy Space Center at approximately 6:35 pm (2235 GMT) local time.
NASA teams and spectators alike were ecstatic as the spacecraft ascended into a radiant sky atop a cascade of flames.
The team, who donned bright orange suits with blue trim as the mission began, includes Americans Reid Wiseman, Victor Glover and Christina Koch along with Canadian Jeremy Hansen.
"We have a beautiful moonrise. We're headed right at it," said Wiseman, the mission commander.
US President Donald Trump praised "our brave astronauts," calling the successful launch "quite something" at the top of his televised address on the war against Iran.
The astronauts are now in orbit around the Earth, where they will remain while performing various checks to ensure the reliability and safety of a spacecraft that has never carried humans before.
They successfully completed "promixity operations" demonstrations, which tested how their Orion capsule can move relative to another spacecraft and included various maneuvers that mimic what would be needed to dock with a lunar lander.
"Great flying with you, Houston. Nice vehicle," said pilot Glover.
Early on teams identified a number of kinks to work out, including "a controller issue with the toilet when they spun it up," said Amit Kshatriya, NASA's associate administrator, during a post-launch briefing.
"We're just getting started," he added.
NASA head Jared Isaacman also noted a temporary communication problem with the spacecraft that had since been resolved.
The astronauts were "safe, they're secure, and they're in great spirits," he said.
Isaacman also emphasized the historic nature of Wednesday's launch: "NASA is back in the business of sending people to the Moon."
- 'Big step for humanity' -
If all goes well the Artemis 2 team is expected to head out Thursday on its three-day journey towards the Moon, which it will then loop around to capture new images and make naked-eye observations.
The voyage should last approximately 10 days in total, and aims to pave the way for a Moon landing in 2028.
Scientist Sian Proctor ventured to Florida's Space Coast to witness the moment along with the approximately 400,000 people local authorities said had gathered to watch.
"I'm just so happy that we're going back to the Moon," Proctor said.
"Everybody should be excited and be following the next 10 days, because this is a big step for humanity."
The mission marks a series of historic accomplishments: it will send the first person of color, the first woman and the first non-American on a lunar mission.
If the plan proceeds as expected, the astronauts will set a record by venturing farther from Earth than any human before.
It is also the inaugural crewed flight of NASA's new lunar rocket, dubbed the Space Launch System.
SLS is designed to allow the United States to repeatedly return to the Moon, with the goal of establishing a permanent base that will offer a platform for further exploration.
It was meant to take off as early as February after years of delays and massive cost overruns.
But repeated setbacks stalled it and even necessitated rolling the rocket back to its hangar for investigation and repairs.
"NASA really needs this win right now," Casey Dreier, chief of space policy at The Planetary Society, told AFP, noting the US space agency's recent budget turmoil and a workforce exodus that have challenged morale.
- 'Competition' -
The current era of American lunar investment has frequently been portrayed as an effort to compete with China, which aims to land humans on the Moon by 2030.
During the post-launch briefing, Isaacman said competition was "a great way to mobilize the resources of a nation."
"Competition can be a good thing," he said. "And we certainly have competition now."
The Artemis program has come under pressure from Trump, who has pushed its pace with the hope that boots will hit the lunar surface before his second term ends in early 2029.
But the projected date of 2028 for a landing has raised eyebrows among experts, in part because Washington is relying on the private sector's technological headway.
Earlier in the day Trump said on Truth Social that the US is "WINNING."
"Economically, Militarily, and now, BEYOND THE STARS. Nobody comes close! America doesn't just compete, we DOMINATE, and the whole World is watching," he posted.
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