The Artemis 1 rocket - named after Apollo's twin sister in Greek mythology - is due to send the space capsule Orion 386,000km into space to lap the Moon, coming as close as 96km to the surface. It will enter another orbit 450,000km from Earth before heading home for a splashdown in the Pacific near San Diego in October.
The capsule's cargo includes test dummies as stand-ins for astronauts: one strapped to vibration and acceleration sensors and two measuring cosmic radiation.
Depending on what happens, astronauts could go on the same flight in two years' time, and a lunar landing for two is the goal before 2026. That would involve SpaceX's Starship craft. The idea is to establish a colony on the Moon, which could lead to the exploration of Mars down the track.
It's a risky operation since the idea is to test the craft against extremes. On the homeward leg it will hit the atmosphere at 40,000 km/h. Orion's 5m-wide heat shield would have to protect astronauts from 2760C re-entry.
"We're going to stress it and test it. We're going make it do things that we would never do with a crew on it in order to try to make it as safe as possible," Nasa administrator Bill Nelson said.
The cost of development and execution for this US$4 billion mission and the others set to follow under the Moon programme in the next three years is about US$93 billion. It's years behind schedule and billions over budget and involves single-use equipment for the rocket.
It's a huge taxpayer-funded investment even as private companies from billionaire space fans are creating reusable rockets. With fierce competition in space exploration, the US is trying to ensure it remains a leader and pushes boundaries. Space also has an importance well beyond commercial interests - a dozen countries have had input into Artemis 1.
This mission comes at a time when the standing of the US in the world is under challenge and eroding as the country appears beset by problems within. And the wider world is struggling with military and political conflict, the climate crisis, cost of living concerns and the coronavirus.
Amid all this gloom, can Nasa pull off a bold, scientifically impressive space feat that reminds people of what's still possible?
Previous Moon missions had a major impact on people's attitudes to both this planet and humanity's place in the universe. This one could inspire people who mainly know about the Apollo achievements from old footage.
This is a step towards getting more footprints on the Moon and, if it's successful, perhaps a confidence booster that moonshots to support efforts to deal with overwhelming problems are still possible on Earth.