It was the first such accident since Nasa turned to private operators to run cargo to the space station. Last month, it awarded its first private "space taxi" contracts for ferrying astronauts to the space station to Boeing and SpaceX.
The rocket's loss posed no immediate problem for the orbiting station's six crew.
Officials say they have supplies for several months and there was no critical cargo on the flight.
As investigators begin their work, they will be looking at the explosion of an AJ-26 engine - the same model as the two propelling the Antares rocket - during tests at Nasa's Stennis Space Centre in Mississippi in May.
The AJ-26 engines were built by Soviet scientists for their failed moon exploration programme in the 1970s, then mothballed for decades.
They were bought and refurbished by a US company and have been used in several rocket launches.
Watch: raw video of the Antares rocket explosion:
Investigators from the US Government and the rocket company Orbital Sciences have given no indication yet of what caused the explosion of the US$200 million ($256 million) Antares and its 2.27-tonne cargo.
Asked about the possible role of the engines, Orbital vice-president Frank Culbertson said: "We need to go through this investigation and be very thorough before we determine whether that's a factor in this or not."
The age and origin of the refurbished engines were already under scrutiny.
Elon Musk, the chief executive of Orbital's competitor, SpaceX, has long warned about the use of decades-old technology, calling it one of the "silly things going on in the market".
Orbital's rocket "sounds like the punch line to a joke", he told Wired magazine. "It uses Russian rocket engines that were made in the Sixties. I don't mean their design is from the Sixties, I mean they start with engines that were made in the Sixties and packed away in Siberia somewhere."
SpaceX, the other company that has a contract to resupply the station, designs its own rocket engines.
But Orbital executives have said there were no more modern alternatives to the technology on which they relied.
Culbertson urged onlookers and local people to stay away from the accident site and not to touch debris or try to pick up souvenirs.
"I do want to caution the public, this is an accident site and it's a rocket and it had a lot of hazardous materials on board that people should not be looking for or wanting to collect souvenirs over.
"If you find anything that washes ashore or came down in your farm or in your yard, please make sure that you call local authorities."
Orbital has a US$1.9 billion contract for eight supply missions to the space station.
Jonathan McDowell, of the Harvard-Smithsonian Centre for Astrophysics, said: "There are two companies to transport supplies to the station. If one fails, the other can take up the slack. This is a bump in the road. But for Orbital this is a huge blow."
