A magnitude 7.2 earthquake hit on Wednesday about 160km west of Caracas, followed less than a minute later by a magnitude 7.5 tremor, according to the US Geological Survey.
The USGS said it would most likely run into the thousands, with a substantial probability of exceeding 10,000.
Interim President Delcy Rodriguez said initial figures did not include casualties from La Guaira state, near Caracas and home to the city's airport, which is the worst affected.
"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 in an appearance on state television early on Thursday.
"I also want to say that this is a true tragedy. From here, we send our message of solidarity, and to those families who have lost loved ones, we reaffirm our condolences and our support in these difficult hours."
The country is focused on rescue efforts, including the arrival in the coming hours of rescue crews from other countries, she said, as she thanked leaders including US President Donald Trump.
Trump said in a post on social media 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.
Three people were killed in the Baruta district in Caracas after two buildings collapsed, the district mayor said on social media.
One person was killed and four buildings had completely collapsed, Gustavo Duque, the mayor of Chacao district in the capital told journalists.
"We have buildings, homes and houses which have collapsed and we are taking care of things with everything we have available in terms of security, civil assistance," Interior Minister Diosdado Cabello said on state television.
Video showed emergency workers climbing through the ruins of a collapsed building in the capital as night fell, while distraught relatives sought help for loved ones believed to be trapped.
A tsunami warning was issued but swiftly cancelled after the danger passed.
Many Venezuelans were at home when the quakes struck during a public holiday.
Leaders from countries including El Salvador, the Dominican Republic and Brazil offered support and sympathy, while the US State Department said it was in touch with Venezuelan authorities and mobilising assistance.
Rodriguez, who has been running the country since the US ouster of Maduro, said she has instructed the foreign ministry to co-ordinate the aid offers.
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 powerful quake caused widespread destruction in the cities of Merida and Caracas in 1812, according to the USGS.
At Caracas' Hospital de Clinicas, staff were asked to double up on the night shift to help treat the injured, a worker there said.
Venezuela's largest airport, in Maiquetia on the coast north of Caracas, was closed due to damages, Rodriguez said.
Classes were cancelled for the rest of the week as authorities began to take stock of the damage.
Venezuela's oil infrastructure did not immediately appear to be affected by the tremors.
Civil protection authorities in Maracaibo, near the large oil hub of Lake Maracaibo, said there were no injuries reported and a worker at the El Palito refinery near Moron - the epicentre of the earthquake - said there had been no damage there.
9°C