The Treasury Department's Office of Foreign Assets Control (OFAC) said Tareck El Aissami has played a "significant role in international narcotics trafficking," a news release said.
"OFAC's action today is the culmination of a multi-year investigation under the Kingpin Act to target significant narcotics traffickers in Venezuela and demonstrates that power and influence do not protect those who engage in these illicit activities," said John Smith, acting director of OFAC.
El Aissami, who was appointed vice president of Venezuela in January, is a former interior and justice minister and governor of the country's Aragua state.
The Treasury Department said he "facilitated shipments of narcotics from Venezuela to include control over planes that leave from a Venezuelan air base, (and) narcotics shipments of over 1,000 kilograms from Venezuela on multiple occasions, including those with the final destinations of Mexico and the United States."
In addition, the department said El Aissami is linked to coordinating drug shipments to Los Zetas, a violent Mexican drug cartel, and provided protection to a Colombian drug lord.
Monday's action imposes sanctions on El Aissami that prohibit anyone in the United States from doing business with him, and freezing any assets the US.
A senior administration official said Monday's sanctions are "not a reaction to El Aissami's role as executive vice president of Venezuela. The designation is the result of a years-long investigation of narcotics trafficking by OFAC."
The official went on to say, "This is a narcotics trafficking case ... and any other kind of activity is not a basis for our action today."
El Aissami is also a subject of a yearlong CNN and CNN en Espanol investigation published last week.
A confidential intelligence document obtained by CNN links El Aissami to 173 Venezuelan passports and ID
's that it says were issued to individuals from the Middle East, including people connected to the terrorist group Hezbollah.
The official who ordered the issuing of the passports, the report said, is El Aissami, who "took charge of issuing, granting visas and nationalizing citizens from different countries, especially Syrians, Lebanese, Jordanians, Iranians and Iraqis."
El Aissami has not responded to multiple requests for comment over several months. CNN reached out to the Venezuelan government Monday night but there was no immediate response.