Senator Robert Byrd, an outspoken critic of US Middle East policy, said on Tuesday that he feared the Syria Accountability and Lebanese Sovereignty Act would be used to justify future military action against Damascus.
"The United States is justified in seeking to apply political and economic pressure on Syria to change its foreign policy," the West Virginia Democrat said.
But he highlighted one particular section of the bill that referred to "hostile actions" by Syria against US-led forces in Iraq.
"I have not seen any evidence that would lead me to believe that it is the government of Syria that is responsible for the attacks against our troops in Iraq," Byrd said.
"Such insinuations can only build the case for military action against Syria, which unfortunately is a very real possibility because of the dangerous doctrine of preemption created by the administration," he said.
"I have not seen any evidence that would lead me to believe that it is the government of Syria that is responsible for the attacks against our troops in Iraq... Such insinuations can only build the case for military action against Syria"
Byrd said the vote in favour of sanctions "could too easily be used to imply congressional support for pre-emptive military action against a rogue state".
"I will vote against this bill because of that dangerous course that it may portend," he said before the vote.
Syria weapons programmes
However, the Senate approved the bill, which easily cleared the House of Representatives last month, by a vote of 89 to 4, alleging Syrian ties to "extremists" and purported efforts to obtain nuclear, biological and chemical weapons.
Earlier on the Senate floor, Foreign Relations chairman Richard Lugar warned Syria that "it is in their interest to recalculate their approach towards the United States".
"Syria shares a 400 mile (650km) border with Iraq," the Indiana Republican said.
"With more than 135,000 US troops deployed in Iraq, Syria needs to reconsider where its future security interests lie."