Although the victory gives Santorum bragging rights, it does not change the overall dynamics of the race; the former Pennsylvania senator still dramatically lags behind Romney in the hunt for delegates to the GOP's summertime nominating convention.
Even so, Santorum's win underscores a pattern in the drawn-out race.
The under-funded under-dog has tended to win in Bible Belt states that include Tennessee, Mississippi and Alabama. Romney – a deep-pocketed, highly organized former Massachusetts governor – has persistently struggled in such heavily conservative regions.
Neither candidate was in the state as Louisiana Republicans weighed in. Nor was former House Speaker Newt Gingrich, who was trailing in Louisiana.
Romney took a rare day off Saturday, with no public events. Santorum spent the day campaigning in Pennsylvania and next-up Wisconsin, which votes April 3 and represents one of his last chances to beat Romney in a Midwestern state.
Early exit polls conducted for The Associated Press and the television networks showed that Santorum's win in Louisiana was one of his strongest performances to date among conservatives, working class voters, and those calling the economy their top issue. And he continued his dominance among white evangelical voters and those looking for a candidate who shares their religious beliefs.
As in previous Southern states, Romney's best showing came among those voters with annual incomes above $100,000 and those who prioritized a candidate's ability to defeat President Barack Obama in November.
The bad economy was the top issue for Louisiana voters. Most were gloomy about prospects for a recovery, saying they felt the economy was getting worse instead of better. While some national surveys suggest Americans are feeling optimistic about economic improvement, just one in eight Republican primary voters said they thought a recovery was under way.
Santorum badly needed a rebound after a decisive Illinois loss to Romney earlier in the week that moved party stalwarts to rally around the front-runner. Many urged Santorum and Gingrich to drop out of the race.
Both refused, and campaigned aggressively in Louisiana in hopes that a victory there would justify them staying in despite Republican worries that the long nomination fight could hurt the party's chances against Obama. The Democratic incumbent faces no serious primary challenge and his reelection campaign already is well under way.
Romney barely campaigned in Louisiana, though his allies spent on TV ads there. Instead, Romney was looking past the results and toward the general election.
"I want the vote of the people of Louisiana so we can consolidate our lead," Romney said Friday while campaigning in Shreveport. He told supporters his campaign wants to focus on "raising the money and building the team to defeat someone that needs to be out of office in 2012, and that's Barack Obama."
Romney is far ahead in the delegate count and on pace to reach the necessary 1,144 delegates before the party's convention in August.
After the Illinois primary March 20, Romney had 563 delegates, according to an Associated Press tally. Santorum had 263, while Gingrich trailed with 135. Texas Rep. Ron Paul had 50.
The Louisiana exit poll found that in a hypothetical choice between just the two top contenders, Santorum's lead over Romney tops 20 percentage points, suggesting the former senator would pick up votes from Gingrich's and Paul's current supporters.
Earlier Saturday, Santorum said he wanted to debate Romney without their trailing competitors on stage.
"This race has clearly gotten down to two candidates that can win the nomination," Santorum told reporters in Milwaukee. "I'd love to have a one-on-one debate."
In the run-up to Louisiana's voting, Santorum found himself on the defensive after suggesting he'd prefer a second term for Obama over a Romney presidency. Santorum was all but forced to walk back those comments, saying less than 24 hours before Louisiana polls opened that "over my dead body would I vote for Barack Obama."
Romney also faced trouble last week when a top aide compared the switch from a primary to a general election campaign to an Etch A Sketch toy, suggesting earlier campaign positions could be easily wiped away.
But most Louisiana voters said they weren't concerned with the comment, with only about one in five in exit polls calling this week's Etch A Sketch controversy an important factor in their vote.
Louisiana has complicated delegate rules: Even though there were 20 delegates at stake Saturday, they are awarded proportionally to the candidates who receive more than 25 percent of the vote.
Most states divide all the available delegates among the candidates who meet the minimum threshold. Louisiana's system is strictly proportional, with any leftover delegates designated as uncommitted, meaning they will be fought for at the state convention.
The next key fight comes April 3 in Wisconsin. Romney's campaign is airing TV ads in the state, and his super PAC allies have plowed more than $2 million into TV advertising there.