Despite the doomsday forecast, the likelihood of the Puente Hills fault generating a large temblor in the next 50 years is slim.
The fault, discovered in 1999, has ruptured at least four times in the past 11,000 years, creating quakes with estimated magnitudes of 7.2 to 7.5.
If a temblor of similar magnitude were to occur today, it would cause 3000 to 18,000 deaths and 120,000 injuries, according to estimates by the US Geological Survey and the Southern California Earthquake Centre.
The projections are meant to help structural engineers, emergency planners and first responders better understand the potential risks if a Puente Hills quake were to occur, scientists said.
The deadliest natural disaster in US history was a 1900 hurricane that decimated Galveston, Texas, killing 6000 to 10,000 people. The costliest was Hurricane Andrew in 1992, which cost insurers more than $20 billion in today's dollars.
The 17 January 1994 magnitude-6.7 Northridge quake, centred in the San Fernando Valley, killed 72 people, injured 9000 and was second to Andrew with more than $15 billion in insured losses.
The consequences would be far more damaging during a major Puente Hills quake because it would hit downtown Los Angeles.
"We need to keep this in perspective ... That being said, we do live in earthquake country and we need to be prepared"
Unlike the Northridge quake, which shook mostly wood-frame houses, the Puente Hills fault snakes beneath older and more vulnerable commercial and industrial buildings.
The estimated casualty and damage numbers are based on the quake striking on a weekday afternoon, when most people are at work. The death toll would be lower if the quake struck at night.
"We need to keep this in perspective," said lead researcher Ned Field of the USGS Pasadena office. "That being said, we do live in earthquake country and we need to be prepared."
Scientists calculated the losses based on software developed by the USGS and the Southern California Earthquake Centre and models from the Federal Emergency Management Agency. Results appear in the May issue of the journal Earthquake Spectra.
The Puente Hills fault, which runs about 40km from downtown Los Angeles to northern Orange County, is formed by the collision of the Pacific and North American plates.
A segment of the fault last ruptured in 1987 with a magnitude-6 earthquake and aftershocks that killed eight people and caused more than $350 million in damage to cities southeast of Los Angeles.