The magnitude 7.8 quake brought down whole apartment blocks in Turkish cities and piled more devastation on millions of Syrians displaced by years of war.
It struck before sunrise in harsh weather and was followed in the early afternoon by another large quake.
In Diyarbakir in southeast Turkey, a woman speaking next to the wreckage of the seven-storey block where she lived said: "We were shaken like a cradle. There were nine of us at home. Two sons of mine are still in the rubble, I'm waiting for them."
She was nursing a broken arm and had injuries to her face.
"It was like the apocalypse," said Abdul Salam al-Mahmoud, a Syrian in the northern town of Atareb. "It's bitterly cold and there's heavy rain, and people need saving."
The earthquake was the biggest recorded worldwide by the US Geological Survey since a tremor in the remote South Atlantic in August 2021.
In Turkey, the death toll stood at 2,316, the Disaster and Emergency Management Authority (AFAD) said, making it the country's deadliest earthquake since a tremor of similar magnitude in 1999 devastated the heavily populated eastern Marmara Sea region near Istanbul, killing more than 17,000.
At least 1,444 people were killed in Syria in Monday's quake and about 3,500 injured, according to figures from the Damascus government and rescue workers in the northwestern region controlled by insurgents.
Poor internet connections and damaged roads between some of the worst-hit cities in Turkey's south, homes to millions of people, hindered efforts to assess and address the impact.
Temperatures in some areas were expected to fall to near freezing overnight, worsening conditions for people trapped under rubble or left homeless. Rain fell on Monday after snowstorms swept the country at the weekend.
More than 13,000 people were injured in Turkey from the quake.
In the Turkish city of Iskenderun, rescuers climbed an enormous pile of debris that was once part of a state hospital's intensive care unit in search of survivors. Health workers did what they could to tend to the new rush of injured patients.
"We have a patient who was taken into surgery but we don't know what happened," said Tulin, a woman in her 30s, standing outside the hospital, wiping away tears and praying.
Turkish President Tayyip Erdogan, preparing for a tough election in May, called the quake a historic disaster and the worst earthquake to hit the country since 1939, but said authorities were doing all they could.
"Everyone is putting their heart and soul into efforts although the winter season, cold weather and the earthquake happening during the night makes things more difficult," he said.
The second quake was big enough to bring down more buildings and, like the first, was felt across the region, endangering rescuers struggling to pull casualties from the rubble.
In Syria, already wrecked by more than 11 years of civil war, the health ministry said 711 people had been killed. In the Syrian rebel-held northwest emergency workers said 733 people had died.
The United Nations says 4.1 million people, many of them displaced by the conflict and living in camps, depend already on cross-border humanitarian aid in northwest Syria and international support efforts are stretched and underfunded.
"Syrian communities are simultaneously hit with an ongoing cholera outbreak and harsh winter events including heavy rain and snow over the weekend," U.N. spokesman Stephane Dujarric told reporters in New York.
In the government-controlled city of Aleppo, footage on Twitter showed two neighbouring buildings collapsing one after the other, filling streets with billowing dust.
Syrian state television showed rescue teams searching for survivors in heavy rain and sleet. President Bashar al-Assad held an emergency cabinet meeting to review the damage and discuss next steps, his office said.
In the Turkish city of Diyarbakir, Reuters journalists saw dozens of rescue workers searching through a mound of debris, all that was left of a big building, and hauling off bits of wreckage as they looked for survivors. Occasionally they raised their hands and called for quiet, listening for sounds of life.
US Secretary of State Antony Blinken spoke by phone with Turkish Foreign Minister Mevlut Cavusoglu on Monday about the earthquake, State Department spokesperson Ned Price said.
He made the call "in the first instance to offer condolences and to make clear...that anything Turkey needed that we could provide, they should pick up the phone and let us know,” Price said. Erdogan said 45 countries had offered to help the search and rescue efforts in Turkey.
The earthquake also halted operations at Turkey's oil export hub in Ceyhan and stopped crude flows from Iraq and Azerbaijan.