A magnitude 7.2 earthquake hit about 160km west of Caracas on Wednesday afternoon, followed less than a minute later by a magnitude 7.5 tremor, according to the US Geological Survey.
Emergency workers scrambled over the debris of collapsed buildings in Caracas as night fell, while distraught relatives sought help for loved ones feared trapped.
Dazed survivors were taken away, some on stretchers.
"When we went downstairs, the scene was like a horror movie," said Maria Alejandra, a resident from a nearby building, who did not give her surname.
"We had to climb over the rubble and everything. The building superintendent with the baby and all the neighbours coming down. But from that building, I only saw that one family got out."
Interim President Delcy Rodriguez said at least 164 people were confirmed dead.
The initial toll did not include those from worst-affected La Guaira state, near Caracas and home to the city's airport, where witnesses' footage showed scenes of panic as ceilings came down.
"Dozens of buildings have collapsed, and we are currently carrying out very intense rescue efforts to save as many lives as God allows us to save," she said on state television early on Thursday.
"La Guaira state is a true tragedy, and has become a disaster zone."
The US Geological Survey, using predictive modelling to estimate the death toll, said it would most likely run into the thousands, with a substantial probability of exceeding 10,000.
A website set up to track missing people and posted on X by leaders from the country's opposition, many of whom are outside the country, listed more than 10,000 people as unaccounted for.
Many Venezuelans were at home when the quakes struck during a public holiday.
Aftershocks rattled Caracas into the early hours of Thursday.
Rodriguez said the country was focused on rescue efforts, including the arrival in the coming hours of rescue crews from other countries, as she thanked leaders including US President Donald Trump.
Trump said in a social media post that the US was ready, willing and able to help in the disaster.
"The two major earthquakes that just hit the great people of Venezuela are both massive in scale and have left a devastating number of deaths," said Trump, who ordered the capture of Venezuelan President Nicolas Maduro in a violent raid in January.
The UN's Venezuela human rights mission urged the government to lift local restrictions on social media, saying it was a "matter of life and death".
In some areas, access had already become available as authorities struggled to cope in a country weighed down by years of economic mismanagement.
Residents across Caracas, which was also hit by a deadly magnitude 6.3 earthquake in 1967, rushed to evacuate as buildings shook.
Leaders from countries including El Salvador, the Dominican Republic, Brazil and Spain offered support and sympathy.
The US State Department said it was in touch with Venezuelan authorities and mobilising assistance.
Venezuela lies in a seismically active zone where the Caribbean Plate meets the South American Plate.
An estimated 30,000 people were killed when a quake caused widespread destruction in Merida and Caracas in 1812, according to the USGS.
School classes were cancelled for the rest of the week.
The city's stock exchange was closed and will be used to help rescue efforts.
The Venezuelan Red Cross said its headquarters had been critically damaged but that it had sent rescue teams to the worst-affected areas.
Venezuela's oil infrastructure did not immediately appear to have been affected.
