President Obama nominated Lew to replace former Treasury Secretary Timothy Geithner last month. Deputy Treasury Secretary Neal Wolin served as acting secretary after Geithner left the post in late January.
"I am pleased that the Senate took bipartisan action today to confirm Jack Lew as our nation's next Treasury Secretary," said President Obama in a statement after the vote. "At this critical time for our economy and our country, there is no one more qualified for this position than Jack."
Lew, 57, has served as Obama's chief of staff since January 2012. He previously served as director of the Office of Management and Budget under two presidents - Obama, from 2010 until he became chief of staff, and Bill Clinton from 1998 to 2001. Lew also dabbled in the private sector, serving as the chief operating officer of the Alternative Investment Unit at Citigroup from 2006 to 2008.
Lew made news early in the nomination process when reporters took note of his unusual loopy signature, a version of which will now appear on U.S. currency. President Obama even poked fun at him at the time.
"I had never noticed Jack's signature, and when this was highlighted yesterday in the press, I considered rescinding my offer to appoint him," Obama joked.
"Jack assures me that he is going to work to make at least one letter legible in order not to debase our currency."
Wednesday's confirmation was the second in as many days for the White House. Former Sen. Chuck Hagel was confirmed as Secretary of Defense on Tuesday.