No astronauts will be on board the capsule when it launches aboard the United States' largest rocket, the Delta IV Heavy made by United Launch Alliance, but engineers will be keenly watching to see how it performs during the four-and-a-half hour flight.
The launch marks the first of a US spacecraft meant to carry people into deep space since the Apollo missions that brought men to the Moon in the 1960s and 1970s.
"We haven't had this feeling in awhile, since the end of the shuttle program, (of) launching an American spacecraft from America's soil and beginning something new," said Mike Sarafin, lead flight director at NASA's Johnson Space Center in Houston.
Tourists and space enthusiasts lined the area known as Florida's Space Coast to see the powerful rocket blast off at sunrise, and 27,000 guests were at Kennedy Space Center for a close up look at the rocket, NASA spokesman Mike Curie said.
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"Thursday is the beginning of that journey, testing key systems - the riskiest systems I would say for Orion - before we have any people on board," said Mark Geyer, program manager for Orion.
The launch at 7:05 am (1735 IST) from Cape Canaveral, Florida, aims to propel 739,000 kilograms of spacecraft, rocket and fuel straight to space, where the capsule will make two laps around the Earth before splashing down in the Pacific Ocean.
The chief contractor of the Orion capsule is Lockheed Martin. The spacecraft was first designed to take humans to the Moon as part of NASA's Constellation program, which was cancelled by President Barack Obama in 2010, in favor or seeking new destinations in deep space.