Saturday's incident was the second US air force crash this week after two F-15C jets collided during training over the Gulf of Mexico on Wednesday, killing a fighter pilot.
The US military said it is investigating the stealth bomber crash.
"Emergency responders are on scene. A board of officers will investigate the accident," said the headquarters of the US air force in the Pacific.
The B-2 was first publicly displayed in 1988 and took its first flight a year later.
The 52-metre wide stealth bomber, which can carry nuclear as well as conventional weapons, has been used in US campaigns over Iraq and Afghanistan.
It emits minimal exhaust, noise and heat, making it hard to detect by radar or infra-red.
Operated exclusively by the US, the aircraft first saw combat in the air war over Kosovo in 1999.
Thomas Czerwinski, of the Pacific air forces public affairs office, said the pilots and the bomber had been in Guam since October 5.
He said: "We can't say anything about the specific mission they were on or why they are flying."
He said that four B-2 bombers have been stationed at Andersen as part of a continuous defence presence in Guam since March 2004, connected with the US-led "war on terror".
Guam is owned by the US, therefore the country would not need the permission of host nations to launch military operation from the island.