At least 100 were killed, and the toll was expected to rise.
Rescue workers and residents frantically searched for survivors under the rubble of crushed buildings in multiple cities on both sides of the border.
In one quake-struck Turkish city, dozens pulled away chunks of concrete and twisted metal.
People on the street shouted up to others inside a partially toppled apartment building, leaning dangerously.
The quake, felt as far away as Cairo, was centred north of the city of Gaziantep in an area about 90 kilometres from the Syrian border.
On the Syrian side of the border, the quake smashed opposition-held regions that are packed with some four million Syrians displaced from other parts of the country by the long civil war.
Many of them live in decrepit conditions with little health care.
Buildings levelled in Turkey earthquake
At least 11 were killed in one town, Atmeh, and many more were buried in the rubble, a doctor in the town, Muheeb Qaddour, told The Associated Press by telephone.
“We fear that the deaths are in the hundreds,” Qaddour said, referring to the rebel-held north-west.
“We are under extreme pressure.”
On the Turkish side, the area has several large cities and is home to millions of Syrian refugees.
Turkish President Recep Tayyip Erdogan said on Twitter that “search and rescue teams were immediately dispatched” to the areas hit by the quake.
“We hope that we will get through this disaster together as soon as possible and with the least damage,” he wrote.
There were at least six aftershocks, and Interior Minister Suleyman Soylu urged people not to enter damaged buildings due to the risks.
“Our priority is to bring out people trapped under ruined buildings and to transfer them to hospitals,” he said.
Tallies from various officials put the toll, for now, at 38 dead in Turkey and 62 in Syria.
At least 130 buildings tumbled down in Turkey’s Malatya province, neighbouring the epicentre, Governor Hulusi Sahin said.
In the Turkish city of Diyarbakir, at least 15 buildings collapsed.
Rescue teams called for silence as they listed for survivors in a toppled 11-storey building.
In north-west Syria, the opposition’s Syrian Civil Defence described the situation in the rebel-held region as “disastrous” adding that entire buildings have collapsed and people are trapped under the rubble.
The civil defence urged people to evacuate buildings to gather in open areas.
Emergency rooms were full of injured, Amjad Rass, president of the Syrian American Medical Society, said.
The US Geological Survey said the quake was centred about 33 kilometres from Gaziantep, a major city and provincial capital.
It was centred 18 kilometres deep, and a strong 6.7 aftershock rumbled about 10 minutes later.
Syria’s state media reported that some buildings collapsed in the northern city of Aleppo and the central city of Hama.
In Damascus, buildings shook and many people went down to the streets in fear.
The quake jolted residents in Lebanon from beds, shaking buildings for about 40 seconds.
Many residents of Beirut left their homes and took to the streets or drove in their cars away from buildings.
The earthquake came as the Middle East is experiencing a snowstorm that is expected to continue until Thursday.
Turkey sits on top of major fault lines and is frequently shaken by earthquakes.
Some 18,000 were killed in powerful earthquakes that hit northwest Turkey in 1999.
