The Syrian government has been accused of carrying out mass killings of thousands of prisoners by the US government.
Diplomat Stuart Jones said Syrian President Bashar Assad's government 'has sunk to a new level of depravity'.
The Trump administration claims the bodies of those killed were burned in a large crematorium outside the capital.
The allegation matches an Amnesty International report released in February which claimed up to 13,000 people - mostly civilians opposed to the government - have been hanged in secret at the prison.
The State Department says about 50 detainees a day are being hanged at Saydnaya military prison, about 45 minutes from Damascus.
It says the crematorium is being used to hide evidence of the extent of the killings.
In February Amnesty International claimed as many as 13,000 people had been hanged in secret.
It claimed the executions have happened at a rate of around 50 a day between 2011 and 2015.
Lynn Maalouf, Deputy Director for Research at Amnesty International’s regional office in Beirut, said: 'The horrors depicted in this report reveal a hidden, monstrous campaign, authorized at the highest levels of the Syrian government, aimed at crushing any form of dissent within the Syrian population.
'We demand that the Syrian authorities immediately cease extrajudicial executions and torture and inhuman treatment at Saydnaya Prison and in all other government prisons across Syria.
'Russia and Iran, the government’s closest allies, must press for an end to these murderous detention policies.'
The US State Department has released newly-declassified photographs showing what it says is a building in the prison complex that has been modified to support the crematorium.
Jones, the acting assistant secretary for Near Eastern Affairs, said the crematorium could be used to dispose of bodies near a prison where tens of thousands of people have been detained during the country's six-year-old civil war.
Jones also said the United States has 'reason to be skeptical' about a deal to set up 'de-escalation zones' brokered by Russia during ceasefire talks in the Kazakh capital Astana last week.
The department released commercial satellite photographs showing what it said is a building in the prison complex that has been modified to support the crematorium. The photographs taken over the course of several years, beginning in 2013, do not definitely prove the building is a crematorium, but they show construction consistent with such use.
One photograph taken in January 2015 shows one area of the building's roof cleared of snow due to melt.