The 32-storey Space Launch System (SLS) rocket was due to blast off from Cape Canaveral in Florida at 1.04am local time on Wednesday to send its Orion capsule on a 25-day test flight around the moon and back without astronauts aboard.
NASA managers on Monday gave the "go" to proceed with flight preparations after 10 weeks beset by multiple engineering difficulties, back-to-back hurricanes and two excursions trundling the spacecraft out of its hangar to the launch pad.
Late in the countdown on Tuesday night, a new potential problem emerged as NASA officials reported what appeared to be a hydrogen leak in the rocket's upper-stage fuel lines, leading launch managers to assemble a special "red team" of technicians to visit the pad with the goal of tightening a key connection.
A short time earlier, NASA chief Bill Nelson had sounded a note of optimism amid fuel-loading operations and other pre-flight activities that had by all accounts gone smoothly.
"I'm feeling good," he told Reuters. "But you don't go until it's ready, and this is a test flight."
Launch attempts on August 29 and September 3 were aborted because of fuel line leaks and other technical problems that NASA has since resolved.
While moored to its launch pad last week, the rocket endured fierce winds and rains from Hurricane Nicole, forcing a two-day flight postponement.
The latest forecast called for an 80 per cent chance of favourable conditions during Wednesday's two-hour launch window, NASA said.
On Tuesday afternoon, launch teams began the lengthy and delicate process of loading the rocket's core-stage fuel tanks with hundreds of thousands of litres of super-cooled liquid oxygen and liquid hydrogen propellant.
Dubbed Artemis I, the mission marks the first flight of the SLS rocket and the Orion capsule together, built by Boeing Co and Lockheed Martin Corp, respectively, under contract with NASA.
Named for the ancient Greek goddess of the hunt - and Apollo's twin sister - Artemis aims to return astronauts to the moon's surface as early as 2025.
Twelve astronauts walked on the moon during six Apollo missions from 1969 to 1972, the only spaceflights yet to place humans on the lunar surface.
The new moon program has enlisted commercial partners such as Elon Musk's SpaceX and the space agencies of Europe, Canada and Japan to eventually establish a long-term lunar base as a stepping stone to even more ambitious human voyages to Mars.
If the mission succeeds, a crewed Artemis II flight around the moon and back could come as early as 2024, followed by the first lunar landing of astronauts, one of them a woman, with Artemis III.
About 90 minutes after liftoff, the rocket's upper stage will propel Orion out of Earth orbit on course for a 25-day flight that brings it to within 100km of the lunar surface before sailing 64,374km beyond the moon and back to Earth. The capsule is expected to splash down on December 11.
Orion will carry a simulated crew of three - one male and two female mannequins - fitted with sensors to measure radiation levels and other stresses that astronauts would experience.
A top objective is to test the durability of Orion's heat shield during re-entry as it hits Earth's atmosphere at 39,429 km/h, or 32 times the speed of sound, on its return from lunar orbit - much faster than re-entries from the space station.
NASA's Office of Inspector General has projected total Artemis costs at $US93 billion by 2025.
