Syrian regime forces have withdrawn from al-Tanf, known as al-Waleed crossing in Iraq, as ISIS gains land - the Syrian Observatory for Human Rights (SOHR) has said.
The loss of al-Tanf comes after ISIS’ takeover of the ancient city of Palmyra on Thursday.
“ISIS controls more than 95,000 sq km of Syria, which is 50 percent of the country's entire territory,” the SOHR said.
The provinces of Deir Ezzor and Raqqa have been under the domination of ISIS and the group have a strong presence in Hasakeh, Aleppo, Homs and Hama.
The UN said it had received reports that regime forces in Palmyra did not let civilians leave the city, before ISIS’ takeover on Thursday.
ISIS’ capture of the ancient city of Palmyra raises concerns about its future since ISIS have previously demolished ancient sites.
Palmyra is one of the most famous world heritage sites in the Middle East, and before the civil war thousands of tourists came to see its Roman-era colonnades.
The group has also been making gains in Iraq, capturing Ramadi after weeks of fighting.
The US has acknowledged the militants' gains are a "setback" for coalition forces targeting ISIS, but US President Barack Obama insisted the US was "not losing" the war with the group.
"There's no doubt there was a tactical setback, although Ramadi had been vulnerable for a very long time," Obama told The Atlantic magazine in an interview published on Thursday.
"The training of Iraqi security forces, the fortifications, the command-and-control systems are not happening fast enough in Anbar, in the Sunni parts of the country,” he added.
White House spokesman Josh Earnest said the problem of ISIS was not going to be solved overnight.
"Until we're able to build up local forces on the ground in Syria who can take the fight to ISIS in their own country… this is going to continue to be a difficult challenge,” he stated.
Eighteen air-strikes have been carried out against ISIS targets in Syria and Iraq since Wednesday by the US-led coalition, according to a statement from the Combined Joint Task Force.