Santorum made his announcement after the weekend hospitalization of his 3-year-old daughter Isabella, and in the face of tightening poll numbers in Pennsylvania -- the state he represented as a U.S. senator -- ahead of the April 24 primary.
"Ladies and gentlemen, we made the decision to get into this race around our kitchen table, against all the odds," Santorum told a news conference, flanked by emotional family members. "We made a decision over the weekend that while the presidential race for us is over, and I will suspend my campaign effective today, we are not done fighting."
The development means Romney, the former Massachusetts governor, is now the certain GOP nominee to take on President Barack Obama in November. While Romney still needs to win several hundred delegates to clinch the nomination, Santorum was his top remaining challenger, and Tuesday's announcement leaves Romney's path unhindered.
Santorum and Romney spoke before the announcement, and Romney told supporters in Delaware that Santorum "will continue to have a major role in the Republican Party."
"We exchanged our thoughts about going forward, and we both have a great deal of interest in seeing the country taken in a very different path," said Romney, who is making his second bid for the GOP nomination. He added, "I look forward to his work in helping to assure victories for Republicans across the country in November."
A senior Santorum source, speaking on condition of anonymity while discussing private conversations, said there is no question his daughter's hospitalization was a major factor in the decision to bow out.
"When you have enough time with your adrenaline down, you start to think about what's really important," the source told CNN. Sitting in the hospital with his daughter, who was born with a potentially fatal chromosomal disorder, for the second time during this campaign put that in perspective for Santorum, especially since the delegate math was not on his side, the source said.
The final decision was made Monday night, while the candidate's family was on the phone with senior strategists John Brabender, longtime adviser Mark Rodgers, campaign manager Mike Biundo and just a few others, the source said.
Sources said Romney asked for Santorum's endorsement right away during their phone conversation. But Santorum's communications director, Hogan Gidley, said there was no guarantee that would happen after what has been a tough and at times bitter campaign.
The senior Santorum source said Romney requested a face-to-face meeting during their talk. Santorum agreed to have one soon, but the source said the time and place have not been set.
In his remarks Tuesday, Santorum never mentioned Romney by name.
Santorum could be a valuable ally for Romney by helping deliver the party's Republican base, which harbors some distrust of the conservative credentials of the former Massachusetts governor.
However, Santorum has consistently said the party needed a true conservative candidate -- himself -- to defeat Obama, and he has relentlessly attacked Romney's support for health care reforms in Massachusetts that included a mandate for coverage similar to the 2010 federal health care law despised by conservatives.
Romney's difficulty with conservatives was evident Tuesday, as two groups known for right-wing stances on social issues commended Santorum's campaign effort but made no mention of Romney.
"Sen. Santorum is an able and worthy competitor, and I congratulate him on the campaign he ran," Romney said in a statement. "He has proven himself to be an important voice in our party and in the nation. We both recognize that what is most important is putting the failures of the last three years behind us and setting America back on the path to prosperity."
Former House Speaker Newt Gingrich, another GOP contender trailing well behind Romney and Santorum, also congratulated Santorum for a "remarkable campaign" that showed the appeal of conservative principles.
Both Gingrich and the other challenger, Texas Rep. Ron Paul, said they intended to stay in the race to the Republican convention in August.
"I think it makes it clearer and simpler," Gingrich said of Santorum's decision while campaigning in North Carolina later Tuesday. "There is one conservative voice in the race and then there is a moderate, and I think [that] makes it easier to articulate and to focus on the platform issues I want to focus on."
In a statement by his campaign, Gingrich said he "humbly" asked Santorum supporters to check out his conservative record on his website Newt.org.
Shortly after Santorum's announcement, the Gingrich website appeared to have crashed, though the reason wasn't known.
The Obama campaign immediately took aim at Romney, with campaign manager Jim Messina saying it was "no surprise that Mitt Romney finally was able to grind down his opponents under an avalanche of negative ads."
"The more the American people see of Mitt Romney, the less they like him and the less they trust him," Messina said in a statement. "While calling himself the 'ideal candidate' for the tea party, he has promised to return to the same policies that created the economic crisis and has alienated women, middle class families, and Hispanic Americans."
Santorum advisers including Gidley said the final decision to suspend the campaign, which allows him to continue raising money and probably keep control of delegates won so far, came Monday night and was based on three factors.
Santorum needed the Texas primary on May 29, with 154 delegates at stake, to be winner-take-all instead of the proportional allocation system based on vote results now in place. However, a complex process for changing the allocation method made that unlikely, they said.
In addition, Santorum needed Gingrich to step aside so Santorum could bring together the conservative right, but Gingrich stayed in the race, they said. Santorum also needed to win Pennsylvania, which remained possible but would require large amounts of time and money against an expected Romney offensive there, the advisers said.
Santorum had canceled two events earlier Tuesday while adding an afternoon event that turned out to be his withdrawal announcement. Gidley said the two morning events were canceled to allow Santorum and his wife, Karen, to "settle in at home" with their young daughter, known as Bella.
Bella was born with Trisomy 18, a serious chromosomal condition that interferes with development. Half of patients with the condition do not survive past the first week of life, according to the National Institutes of Health.
Santorum mentioned the girl several times in his comments, saying he was inspired by people who cited the need to speak up for people with disabilities and others being marginalized by the nation's present direction and problems.
"Against all odds we won 11 states, millions of voters, millions of votes," Santorum said, adding he found a "deeper love for this country" through the campaign.
"It was a love affair for me going from state to state and seeing the differences but seeing the wonderful, wonderful people of this country who care deeply about where this country is going in the future, who care deeply about those who are out there paddling alone who are feeling left behind and in some respects are feeling hopeless and want to do something," he said.
Meanwhile, a poll Tuesday shows Romney trailing Obama in a head-to-head matchup, though voters remain split on which presidential contender is best equipped to handle the economy.
The survey, from Washington Post/ABC News, showed 51% of Americans would choose Obama if the election were held now, compared to 44% for Romney.
According to the polling data, Americans are divided on which candidate would best handle economic issues: Forty-seven percent favored Romney while 43% named Obama. When asked which man would be better at creating jobs, 46% named Obama and 43% said Romney. Both margins were within the poll's 3.5 percentage point sampling error.
Voters were less divided on other key issues. Fifty-three percent said Obama was best poised to handle international affairs, compared to 36% who said Romney. Conversely, when asked which man would do a better job of reducing the federal deficit, 51% said Romney and 38% said Obama.
In terms of likability, Obama held a clear advantage, with 64% of Americans polled saying the president was a more friendly and likable person, a nearly 2-to-1 advantage over Romney, who was at 26%.
The serious gender gap between the two candidates -- also seen in recent Gallup and CNN/ORC polls -- also appeared in the new poll. Obama had the support of 57% of women, compared to 38% who said they backed Romney, while the former Massachusetts governor had the backing of 52% of men, compared to 44% who backed Obama.
Among another important voting block, independents, the poll shows a much tighter race, with 48% backing Romney compared to 46% for Obama, also within the survey's sampling error.
Romney has used a huge advantage in money and organization to build his lead over Santorum, Gingrich and Paul. In particular, the Romney campaign and the super PAC supporting it have spent millions of dollars on negative ads in the run-up to major primary and caucus votes so far.
Gingrich admitted Sunday that Romney was the likely nominee.
"I think you have to be realistic," Gingrich said on "Fox News Sunday." "Given the size of his organization, given the number of primaries he's won, he is far and away the most likely Republican nominee."
CNN's latest estimate of the GOP delegate tally shows Romney with 659, Santorum with 275, Gingrich with 140 and Paul with 71. It takes 1,144 delegates to clinch the nomination.
New York, Connecticut, Rhode Island and Delaware vote on April 24, in addition to Pennsylvania. In all, 231 delegates are up for grabs in the five states.
The goal now for Gingrich and Paul is to prevent Romney from reaching the 1,144-delegate threshold before the convention. While all but conceding the GOP race, Gingrich said Sunday he won't give up on trying to influence the party's platform that emerges going into the general election.
"I think platforms matter in the long run in the evolution of the party," the former House speaker said. "And the party is more than just a presidential candidate -- it's Senate candidates, House candidates, state legislators."
Gingrich also said he has already talked to Republican National Committee Chairman Reince Priebus about working in the fall "to help defeat Obama any way I could -- whatever the team thinks I can do to be helpful, I would do."
Beyond that, he said he wouldn't want to serve in a Romney administration and would rather "go back to a post-political career."