Mr Gingrich won 41% of the vote, Mitt Romney took 27%, Rick Santorum, a former senator, got 17% and Texas congressman Ron Paul, 13%.
It marks a significant turnaround from Mr Gingrich's earlier poor showings in Iowa and New Hampshire and suggests the race could continue for months - starting with the next battleground, Florida.
The victory means three different candidates have won the first three contests in the state-by-state battle for the Republican presidential nomination to face Democratic President Barack Obama on November 6.
Mr Santorum won the Iowa caucuses on January 3 and Mr Romney won the New Hampshire primary on January 10.
Mr Gingrich told supporters in South Carolina it was "very humbling and very sobering to have so many people who so deeply want their country to get back on the right track".
"This is the most important election of our lifetime... with your help we are now moving on to Florida and beyond," he said.
Mr Romney congratulated Mr Gingrich on a "hard-fought" campaign but pledged to continue fighting for every vote in every state.
"We're now three contests into a long primary season," he said. "This is a hard fight because there's so much worth fighting for.
"We've still got a long way to go, and a lot of work to do."
:: More from Sky News on the Republican primaries
Sky reporter Hannah Thomas-Peter, in South Carolina, said: "We'll have to see if Newt Gingrich can continue his momentum.
"Make no mistake - this was a really bad day for Mitt Romney."
The vote follows an eventful week in which Mr Romney contended with difficult questions about his finances and Mr Gingrich had to brush off claims by an ex-wife that he had asked her for an "open marriage".
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