Yellen, described by US President Barack Obama as one of the country's most respected economists, is expected to be sworn into office on February 1.
She will replace Ben Bernanke as the Chair of the Federal Reserve.
The Senate voted 56-26 to confirm 67-year-old Yellen as the first woman to lead the Federal Reserve.
"With the bipartisan confirmation of Janet Yellen as the next Chair of the Federal Reserve, the American people will have a fierce champion who understands that the ultimate goal of economic and financial policymaking is to improve the lives, jobs and standard of living of American workers and their families," Obama said, soon after Yellen's confirmation.
"As one of our nation's most respected economists and a leading voice at the Fed for more than a decade and Vice Chair for the past three years, Janet helped pull our economy out of recession and put us on the path of steady growth," Obama said in a statement.
With the confirmation of Yellen as the first Chairwoman in the 100-year history of central bank, the Senate has taken a momentous and much-needed step to ensure our country continues to be the engine of a thriving global economy, Nancy Pelosi, the House Democratic Leader, said.
Pelosi said Yellen will lead the Federal Reserve with an extraordinary level of discipline, determination, and expertise on America's economy.
"As a Professor Emeritus at University of California- Berkeley, she quickly rose as a respected leader in the field of economics and later worked within the Federal Reserve system for nearly ten years -- as a governor, as the President and CEO of the Federal Reserve Bank of San Francisco, and currently as vice chair," she said.
US Treasury Secretary Jacob Lew said with many years of experience in economics and at the Federal Reserve, Yellen is a proven leader who will assume the vast responsibilities of this position with a steady hand.
"Janet is not only enormously qualified to take on this role, she is also widely respected for her keen mind, sound judgement and independence. At the Federal Reserve, she has been a vital and often prescient voice," he said.
Image: Janet Yellen
America's economic woes are far from over
Fed committed to easy policy for as long as needed: Bernanke
World central bank policymakers change gears
US Fed begins taper but suggests easy policy
The Indian American who may represent Silicon Valley in the US Congress