All eight crew members aboard were presumed to have been killed, the base said.
The eight-engine, jet-powered aircraft, built to carry nuclear and conventional bombs, was on a routine test mission when it went down, Edwards said in a statement about four hours after the crash on Monday morning.
Aerial video footage of the crash scene, about 160km north of Los Angeles, showed a charred, smouldering patch of the desert floor roughly the size of a football field as an emergency vehicle was seen driving along the site's perimeter.
There were no large pieces of debris readily visible in the footage.
"An Air Force B-52 Stratofortress carrying eight people on a routine test mission crashed today after take-off at 11.20am (PDT). Initial indications are that the crash was not survivable," the base said in an update posted on X.
It said an emergency response team was on the scene, and officials were "working to account for all personnel".
The Air Force said the cause of the crash was under investigation.
The Stratofortress, designed and built by Boeing, is a long-range, subsonic aircraft that has long served as the backbone of the US crewed strategic bomber force, according to the military.
The swept-wing aircraft is capable of carrying munitions, including cluster bombs and gravity bombs, at altitudes of up to 15,000m, according to an Air Force fact sheet.
In a conventional conflict, the B-52 can perform strategic attack, close-air support, air interdiction, offensive counter-air and maritime operations, the fact sheet said.
Monday's incident marked the first crash of a B-52 Stratofortress since the same type of bomber crashed on the island of Guam in May 2016, according to the Bureau of Aircraft Accidents Archives, a Geneva-based organisation that collects global aviation accident data. All seven crew members aboard that aircraft survived.
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