The Associated Press called the race for the Republican incumbent shortly after polls closed Tuesday night.
The call was based on an analysis of voter interviews, conducted for The Associated Press by Edison Media Research and Mitofsky International.
The re-election shows Graham overcame Republican misgivings about his role in failed immigration legislation. The senator spent most of his campaign on the road with John McCain and spent Election Day in Arizona.
Challenger Bob Conley was a newcomer to state politics and the Democratic Party. He tried to run to the right of Graham and did not curry favor from state Democrats.