The small-business bill, which was approved by the House last week, is likely the last economic stimulus before the midterm elections.
The legislation includes $12 billion in tax breaks and a $30 billion fund to encourage community banks to make loans to small businesses.
The Obama administration criticized Republicans for holding up aid to small businesses. Republicans argued Democrats had not made the legislation a top priority for most of the year.
The Senate voted 61-38 in support of the vote. Sens. George Voinovich (Ohio) and George LeMieux (Fla.) were the only Republicans to vote in favor of the legislation.
The House passed the legislation last week on a 237-187 vote, with 13 Democrats opposing the bill. Rep. Walter Jones (N.C.) was the sole Republican to support the bill.
As the economic recovery showed signs of slowing in the late summer, Obama proposed $50 billion in new spending on infrastructure and billions of dollars in additional tax breaks.
Obama's recent spending and tax proposals have made little headway on Capitol Hill, leaving the small-business bill likely the last economic stimulus effort Obama will enact before the November elections.
The House and Senate are slated to adjourn at the end of this week.