Lawmakers voted 68 to 27 to confirm Fischer, a dual US-Israeli citizen who until last year served as governor of Israel's central bank. They will examine his nomination as vice chairman next month.
Members of the Senate Banking Committee last month gave the green light for Fischer, who was tapped by President Barack Obama in January to be Fed Chair Janet Yellen's number two.
At the time of the appointment, Obama described Fischer as having "one of the world's leading and most experienced economic policy minds."
Fischer would join Yellen at the head of the Fed at a time it seeks to unwind a huge balance sheet of some $4 trillion by slowly phasing out a program of bond purchases known as quantitative easing.