The US Geological Survey said the 7.8 magnitude tremor struck at a depth of 17.9km (11 miles) near the city of Gaziantep.
According to the latest reports, at least 3,400 deaths were reported in Turkey, while 1,500 people died in Syria.
There are fears the death toll will rise sharply in the coming hours.
Many buildings have collapsed, and rescue teams have been deployed to search for survivors.
The tremor was also felt in Syria, Lebanon and Cyprus.
Second large earthquake strikes Turkey and Syria less than 12 hours after first
Turkey reports that a second massive earthquake in less than 12 hours has hit the southeast of the country. State media in Syria have also said that Damascus was affected by the latest large quake, although details remain scant.
The European Mediterranean Seismological Centre (EMSC) said that preliminary data showed the quake measured 7.7 magnitude on the Richter scale, and was 67 km (42 miles) north north-east of Kahramanmaraş, Turkey, at a depth of 2 km. Turkey’s Disaster and Emergency Management Authority stated that it was slightly smaller at 7.6 magnitude and at a greater depth.
"I was writing something and just all of a sudden the entire building started shaking and yes I didn't really know what to feel," Mohamad El Chamaa, a student in the Lebanese capital Beirut, told foreign media.
"I was right next to the window so I was just scared that they might shatter. It went on for four-five minutes and it was pretty horrific. It was mind-blowing," he said.
Turkish seismologists estimated the strength of the quake to be 7.4 magnitude. They said that a second tremor hit the region just minutes later. Turkey lies in one of the world's most active earthquake zones.
In 1999, more than 17,000 people were killed after a powerful tremor rocked the north-west of the country.
Turkish President Tayyip Erdogan said 45 countries had offered to help with the search and rescue efforts.
The United States was "profoundly concerned" about the quake and was monitoring events closely, White House national security adviser Jake Sullivan said on Twitter. "We stand ready to provide any and all needed assistance," he said.
This is a developing story............