The move "will meaningfully dent the (Venezuelan) government's cashflow," wrote Risa Grais-Targow, Latin America director at Eurasia Group, a political consultancy.
"PDVSA will have to deeply discount its barrels in order to displace the heavy Middle Eastern crudes that those refineries are currently processing. This will also carry extra transportation costs," she added.
Washington's sanctions are aimed at putting pressure on socialist leader Nicolas Maduro to step aside.
Venezuela was thrust into a political crisis last Wednesday, when opposition leader Juan Guaido declared himself the rightful interim president, prompting world powers including Washington and many Latin American nations to recognize him as the country's "acting president." The move spurred Maduro to break relations with the U.S. and order all American diplomatic personnel to leave the country.
The latest sanctions will transfer control of Venezuela's oil wealth to forces that oppose Maduro and deprive the strongman of resources that could prolong his grip on power.
According to National Security Advisor John Bolton, the move will block some $7 billion in state assets, and represents around $11 billion in lost export revenue from the U.S. market.
That will deal a further blow to PDVSA.
The firm's financial situation was already "on a knife-edge" with only about half of its crude oil exports generating cash revenues, said Eileen Gavin, senior politics analyst at Verisk Maplecroft, a risk consultancy.
The rest is shipped largely to China, as payment in kind for a decade of multi-billion dollar lending, Gavin said in a recent note.
While PDVSA will be able to find new markets for its crude, refineries in China and India are the "only ones" outside of the U.S. Gulf Coast with the capacity to refine Venezuela's particular type of heavy, sour crude, according to Eurasia Group's Grais-Targow.
The oil-rich South American country will likely seek to sell the crude oil at a discount to other Asian countries as well, traders told Reuters last week.
Under the new sanctions, U.S. companies can continue to purchase Venezuelan oil, but the payments must be held in an account that cannot be accessed by the Maduro regime.
Treasury Secretary Steven Mnuchin said PDVSA has long been used by officials and businessmen for embezzlement and corruption. The sanctions will prevent the nation's oil wealth from being diverted to Maduro and will only be lifted when his regime hands control of PDVSA to a successor government, he added.
Venezuela is a major supplier of heavy oil, which is largely used to produce distillates like diesel and jet fuel.
— CNBC's Tom DiChristopher and Reuters contributed to this report.