Incumbent Senator Bill Nelson won reelection to a third term, defeating Republican U.S. Representative Connie Mack IV (whose father, Connie Mack III was Nelson's direct predecessor in that Senate seat) by 13%, winning 55% to 42%.

This is also the last time a Democrat carried the following counties in a statewide election: Brevard, Flagler, Franklin, Hamilton, Hendry, Hernando, Liberty, Madison, Manatee, Marion, Okeechobee, Pasco, Polk, Sarasota, and Volusia.

Early on in the race, Nelson appeared to be vulnerable, with some earlier polls showing Mack leading.

Only one debate was held, hosted by Leadership Florida/Florida Press Association occurred on October 17 at the Nova Southeastern University campus in Davie.

In early October 2012, Crossroads GPS announced it would launch a $16 million advertising buy in national races, of which four were this and three other Senate elections.