"We will fight if you dare to set foot in Venezuela," Padrino Lopez warned the US government in a statement released by state-run media, Xinhua reported.
Venezuela is under a siege that aims to provoke internal chaos and undermine the nation's political leadership, said the defense chief.
"The announcement of these naval deployments in Caribbean waters is nothing more than a show of force, a way of marking territory, so that other powers will not take control of the Caribbean Sea," he said, referring to US military maneuvers in the region.
The Venezuelan Armed Forces are patrolling the country's maritime borders and airspace in response to President Nicolas Maduro's call to strengthen the Bolivarian National Militia, said the official.
Padrino Lopez added that 15,000 military personnel have been deployed to Venezuela's western region.
The minister also highlighted the military's domestic security efforts, noting that anti-drug operations have led to the destruction of over 30 criminal outposts and illegal boat-building facilities.
Tensions in the Caribbean Sea have escalated after the United States deployed warships near the coast of Venezuela earlier this month, which Washington describes as part of its strategy to fight the international drug cartels.
Several leaders in the region, including Mexican President Claudia Sheinbaum and Colombian President Gustavo Petro, criticized US military maneuvers near Venezuela in the Caribbean Sea.