There were no immediate reports that the militants were destroying the ruins, but just as worryingly, Palmyra was the second big victory for ISIS in less than a week.
For days, the ancient city was the center of fierce fighting. CBS News correspondent Clarissa Ward says videos posted by activists right up until Thursday morning showed clouds of smoke hovering ominously over ruins that date back 2,000 years.
The Syrian army tried to push back the Sunni ISIS militants for days, pounding their positions with airstrikes from fighter jets, but it wasn't enough. Wednesday night, ISIS claimed victory.
The fall of Palmyra is a strategic loss for the Syrian regime; the city is surrounded by gas fields and according to some analysts, could enable the terror group to claim even more territory.
"Palmyra is very strategically situated and can now be used as a launching pad for further territorial pushes towards Homs and Damascus," said Matthew Henman, of IHS Jane's Terrorism and Insurgency Centre. "The capture of Palmyra leaves the Islamic State strongly placed to make more territorial gains from Assad, at a time when the government is heavily occupied in vital battles in the north
But as Ward reports, it also puts the future of some of the country's most precious cultural heritage in jeopardy.
ISIS has destroyed many cultural relics in territory that it has seized, condemning them as "un-Islamic."
The militants have also looted and crudely excavated some sites, profiting in the sale of stolen antiquities has become a big money-maker for the group.
Assaad Seif is an archaeologist with Lebanon's Directorate General of Antiquities in Beirut, where a lot of those looted artifacts pass through. He showed CBS News some pieces that had recently been seized by Lebanese police.
"When we deal with culture and when we deal with heritage, it's something else that is valuable," he said, explaining that what is lost when antiquities are destroyed is an entire peoples' "culture, heritage their history."
Ward notes that Palmyra fell just days after the Iraqi city of Ramadi was seized by ISIS; two big victories in two different countries that confidently dispel any thoughts that the militant group might have been seriously set back by losing Tikrit, in northern Iraq, or by the U.S.-led campaign of airstrikes against them.
The U.S. military's Central Command (CENTCOM) said Wednesday that there had been no U.S.-led coalition strikes in the vicinity of Palmyra, as it had been an area under control of the Assad regime. A CENTCOM official told CBS News the command was "aware" of the open source reporting that ISIS was in control there.
Thus far, airstrikes in Syria by the U.S. and its allies have largely avoided targets which could be beneficial to President Assad's opposing forces.
Palmyra is now a front line in the war from which ISIS could seek to press its gains against the regime -- putting the Obama administration in the awkward position of not wanting to help its original enemy in Syria by attacking the more recently-evolved threat of ISIS, which continues to espouse violence against Americans and the U.S. homeland.