CNN and NBC television networks projected the results, the former first lady defeating Republican challenger John Spencer.
Ms Clinton had been expected to win easily, having outpolled Mr Spencer, a former mayor, by more than 30 points in a state where registered Democrats outnumber Republicans by a 5-3 ratio.
With her second Senate term in hand, Ms Clinton now faces widespread speculation that she will pursue higher political office.
Prior to Election Day, Ms Clinton insisted that she was concentrating on her re-election campaign and had not made a decision on a White House bid.
New York Republicans tried to make an issue of her possible higher political ambitions but most voters indicated it made no difference in whether they would re-elect her to the Senate.
Political analysts noted Ms Clinton has tried to broaden support in New York, where voters tend to have more conservative leanings upstate and outside of New York City, with moderate positions during her first term.
An anti-war candidate challenged Ms Clinton for the Democratic Senate nomination, taking issue with her vote in Congress to support the US-led war in Iraq, but he gained little traction.
Ms Clinton enjoyed fat campaign coffers, having raised US$35 million (A$45.3 million) while her opposition, Mr Spencer, raised less than US$4 million.
She also enjoyed celebrity status during the race, particularly when her husband, former President Bill Clinton, joined her on the campaign trail.