The controversial amendment, which sought to constitutionally define marriage as an institution solely between a man and a woman, failed to win the 60 votes necessary in the Senate to keep the measure alive. Six Republicans joining 43 Democrats and one independent in defeating the amendment by a 50-48 tally.
Sen. Lindsey Graham, R-S.C., supported the amendment.
"A handful of liberal judges in Massachusetts should not be allowed to change the definition of marriage for the rest of the country," Graham said, referring to the Massachusetts Supreme Court decision that opened the door to same-sex marriages in the state. "Unfortunately, that is the situation we find ourselves in today."
Though he has voiced his opposition to gay marriage, Sen. Fritz Hollings, D-S.C., voted against the amendment.
"We don't have domestic law in the Constitution," he said. "We don't talk about divorces and alimony in the Constitution and we shouldn't be talking about this either."
The Republican candidate for Hollings' seat, to be vacated at the end of the year, offered his support for the amendment.
"Since the dawn of time, traditional marriage -- the union between one man and one woman -- has been the building block of civilization, and at no point in our nation's history has that foundation been under more severe attack than now," said U.S. Rep. Jim DeMint, R-S.C.
The House of Representatives will consider the measure in September.
"Same-sex marriage is troubling to me because it is impossible to grant this right without also endorsing and legitimizing the homosexual lifestyle," DeMint said.
Leading up to the vote, South Carolina gay rights groups wrote the senators expressing their objections to the legislation.
"Not only the gay and lesbian community but also the straight community are appalled that the Senate (took) time out during this difficult moment in the nation's history and spent our tax dollars arguing about same-sex marriage," said Warren Redman-Gress, executive director of the Alliance for Full Acceptance, a South Carolina gay rights organization.
During debate Monday, Sen. Rick Santorum, R-Penn., said the amendment's goal was to protect families and children, not to limit anyone's rights.
"Marriage is already in tough shape," he said. "Further diluting and debilitating marriage is not the answer."
But without the right to marry, gay couples are not eligible for the benefits associated with marriage. For example, children of gay couples cannot receive Social Security survivor benefits or health insurance coverage from a non-biological parent.
"The suffering that people experience is very real when your relationship is not recognized," Redman-Gress said.
Proponents of the amendment expected it to fail in the Senate but said the debate surrounding it would raise public awareness for future attempts. Opponents countered that the amendment was just an election-year political ploy.
"It's one of these political footballs that gets thrown around," Redman-Gress said. "It's really disheartening."