AFP journalists saw the naval vessel passing through one of the canal's locks at around 9:30 pm (0230 GMT Saturday) and navigating east toward the Atlantic.
The United States has said the deployment of warships to the southern Caribbean, near Venezuela's territorial waters, was an anti-drug trafficking operation.
"I didn't know the ship was going to pass... I was surprised," Alfredo Cedeno, a 32-year-old health technician, who took photos of the cruiser, told AFP.
The Lake Erie had been moored for the past two days at the Port of Rodman, at the canal's Pacific entrance.
Washington has accused Venezuelan President Nicolas Maduro of leading a drug cartel and has doubled the bounty for his capture to $50 million.
The United States has, however, made no public threat to invade Venezuela.
Caracas announced on Monday the deployment of 15,000 security forces to the Colombian border for anti-drug trafficking operations.
A day later, Venezuela announced that it would patrol its territorial waters with drones and navy ships.
Maduro also claimed to have mobilized more than four million militia members in response to US "threats."
The 567-foot-long (173 meters) USS Lake Erie displaces 9,800 tons and is based in the port of San Diego, California.
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