The Big One will strike along the San Andreas fault line in California, where the Pacific and North American tectonic plates meet.
The area is a major seismic hot spot, where catastrophic earthquakes strike every few hundred years.
John Vidale, director of the Southern California Earthquake Centre, warned the Big One will one day hit California.
But there is no telling when this will happen, he added.
The earthquake expert told Newsweek: “When we look at the history of the fault, we can see these big earthquakes have happened many times over the last few thousand years, so yeah, it’s an inevitability.
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“We just don’t know if it’s going to be now or two hundred years from now.”
The Californian Big One is a hypothetical earthquake on a power scale between magnitude seven and magnitude eight.
The last Big One struck in the heart of San Francisco in 1906, tearing through a 296 mile-long (477 km) stretch of the San Andreas fault line.
The earthquake killed around 3,000 people and razed entire sections of the city to the ground.
Various estimates suggest the force of the earthquake was somewhere between magnitude 7.7 and magnitude 8.3.
Another major earthquake on this scale broke out in Southern California in 1857, peaking around magnitude 7.9.
Mr Vidale has now warned another Big One could have a grave impact on the burgeoning Californian economy.
He said: “The impact of the northern Big One would be tremendous – I mean the San Andreas runs right through San Francisco. It’s quite closer to San Francisco than it is to Los Angeles.
“Downtown San Francisco is vulnerable – some of the oldest buildings survived the shacking back in 1906, but that doesn’t mean they’d be safe in the next earthquake by any means.
“Many of the buildings are built close to the fault and on kind of soft ground that might liquify.
“A southern Big One would likely strike a little further away from the heart of Los Angeles, so the impact might be smaller.”
The earthquake expert warned the Big One could create deadly landslides, chemical spills and raging fires.
But the United States Geological Survey (USGS) claims there is no “scientifically plausible” to predict when a future earthquake will strike.
California sits on the so-called Pacific Ring of Fire – a hotbed of seismic and volcanic hotspots running around the basin of the Pacific Ocean.
The Ring of Fire covers a 25,000 mile-long (40,000 km) arc from the southern tip of South America all the way up through the US west coast, Japan, Southeast Asia and New Zealand.
About 75 percent of all of the world’s active volcanoes are found in this belt of tectonic activity.
Ninety percent of the world’s earthquakes occur in the Ring of Fire and 81 percent of the world’s strongest quakes happen there.
In the last 11,700 years, all but three of the largest ever volcanic eruptions blew up in the Ring of Fire.