Attonery General Eric Holder has said US force could launch a deadly drone strike against a target on home soil if there was an "extraordinary circumstance".
In a letter to Republican Senator Rand Paul, the nation's top Justice Department official stressed that US military and intelligence agencies had "no intention" of carrying out such an attack for the moment.
"The question you have posed is... entirely hypothetical, unlikely to occur and one we hope no president will ever have to confront," Holder wrote, in a later dated on Monday.
At least three Americans have been killed in US drone strikes, including Al-Qaeda propagandist Anwar al-Awlaki in Yemen.
As part of the confirmation process for President Barack Obama's pick for the head of the CIA, Paul had sought information on the president's authority to authorise lethal drone strikes.
"It is possible, I suppose, to imagine an extraordinary circumstance in which it would be necessary and appropriate under the Constitution and applicable laws of the United States for the president to authorise the military to use lethal force within the territory of the United States," Holder said in the letter.
Brennan, who has worked in the CIA for a quarter century, is known as the chief architect of the drone war, and he faced numerous questions at his confirmation hearing over the "targeted killings".
His nomination passed a key hurdle on Tuesday with the Senate Intelligence Committee voting by 12 votes to three to approve Brennan to head the CIA. A full Senate vote is expected this week.
The approval came after the White House decided to give Congress secret Justice Department memos that may have been used to justify the president's ability to authorise the targeted killing of Americans.
Paul, who has long questioned the legality of the government's use of lethal force - including strikes by unmanned drones - against US citizens, expressed alarm at Holder's response.
"The US attorney general's refusal to rule out the possibility of drone strikes on American citizens and on American soil is more than frightening," he said.
"It is an affront (to) the Constitutional due process rights of all Americans."
Paul had previously asked for Brennan's views on drone strikes. The nominee wrote back that the CIA has no authority to launch such attacks on US soil.