At least 21 people have been killed so far in the Trump administration's attacks, which it has said are necessary to protect the United States from a scourge of smuggled narcotics, particularly from Venezuela.
But many experts question the legality of using lethal force in foreign or international waters against suspects who have not been intercepted or questioned.
The resolution in the Senate was rejected late Wednesday with 48 votes for and 51 against.
Adam Schiff, a Democratic senator who led the initiative, said before the vote that the strikes "could set off an unintended conflict with Venezuela."
Nicolas Maduro, president of the oil-rich nation, has criticized the US military action as "armed aggression to impose regime change."
Trump boasted on Sunday that lethal strikes on small boats near the Venezuelan coast have been so successful "there are no boats" left in that area of the Caribbean.
He added that military action could be expanded to land routes used by apparent drug traffickers.
Rand Paul, one of two Republicans who supported the text in the Senate, said beforehand that he wanted to ensure that military action abroad had congressional approval.
"The US should not be blowing up boats without even knowing who's on them," he wrote on X.
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