With 60 percent of precincts reporting, the former U.S. senator from Pennsylvania received 38 percent of the vote, followed by former Massachusetts Gov. Mitt Romney with 28 percent, former U.S. House Speaker Newt Gingrich with 23 percent and U.S. Rep. Ron Paul of Texas with 9 percent.
CNN and other TV networks projected Santorum would win Tennessee based on exit polling and early returns.
Santorum had led in the polls, and Romney supporters said they hoped a win in the Volunteer State would show support in the South, a region where Romney has struggled.
Voters in the mostly rural state voted contrary to Republican Gov. Bill Haslam, U.S. Sen. Lamar Alexander and state House Speaker Beth Harwell, who backed Romney. Haslam chaired Romney's campaign in the state, returning a favor from 2010, when Romney backed Haslam's gubernatorial bid.
Gingrich made a solid push in Tennessee, campaigning in Nashville while Romney and Santorum focused on Michigan.
Santorum, who has emphasized social issues and blue-collar economics as he works to attract conservatives unhappy with Romney, was also projected to win in Oklahoma, The Wall Street Journal reported.
Tennessee has 55 delegates up for grabs, the third-most among the 10 Super Tuesday states. Candidates must gain 20 percent of the vote statewide or within the nine congressional districts to qualify for a share of the delegates.
The state also has three so-called super delegates, who are unbound.