"The ultimate goal of air strikes should be to establish and defend safe havens in Syria, especially in the north, in which opposition forces can organize and plan their political and military activities against Assad," McCain, an influential Republican, said in remarks on the Senate floor.
McCain has previously called for efforts to arm the Syrian opposition. But he said on Monday the help Syrian rebels needed most urgently was "relief from Assad's tank and artillery sieges in the many cities that are still contested" in Syria.
The battered city of Homs is "lost for now," but other cities are not, the 2008 Republican presidential nominee said.
The Obama administration has thus far stressed seeking a political solution to the crisis. Last month, the White House said it did not rule out "additional measures" if a political solution turned out to be impossible.
"The time has come for a new policy," said McCain, who lost the race for the White House to Democrat Barack Obama in 2008. "Assad needs to know that he will not win."
"These safe havens could serve as platforms for the delivery of humanitarian and military assistance - including weapons and ammunition, body armor and other personal protective equipment, tactical intelligence, secure communications equipment, food and water and medical supplies," said McCain, the ranking Republican on the Senate Armed Services Committee.
He said the safe havens could also help the Free Syrian Army and other armed groups in Syria train and organize themselves into more cohesive and effective military forces, "likely with the assistance of foreign partners."
While there would not be a U.N. Security Council resolution on Syria because of Russian and Chinese opposition, McCain said, the United States should seek the active involvement of key Arab partners such as Saudi Arabia, and NATO allies such as Turkey.
The United Nations says over 7,500 civilians have died in Syria's nearly year-long crackdown on protests against Assad's government.