Projections had Andrews ahead by about 4 points with 84 percent of the vote counted, and NBC's call came at 9:59 p.m. Vote-share figures differ slightly between tallies, with one putting her at 51 percent to Graham's 46.8 percent. Graham trailed the vote totals her brother had reached in the state. Donald Trump won South Carolina by 18 points in 2024, and Lindsey Graham won his 2020 race by 10 points despite spending hundreds of millions of dollars.

Darline Graham is the sister of Lindsey Graham, the Republican senator who died in July while seeking a fifth term. Gov. Henry McMaster, a Republican, appointed her to the seat, and she served as interim senator, ran for a full term and won a special primary. It was the first time a sibling has replaced a senator who died in office. Trump personally selected her to succeed her brother, encouraged her to run for a full term, endorsed her and campaigned for her, including in the closing days of the race.

Republicans were initially confident of holding the seat. The shift came from Graham's status as a political novice, Andrews' fundraising and national discontent with Republicans and Trump. Voter surveys found about two-thirds of voters said Graham lacked the right experience, and about 7 in 10 of those voters backed Andrews. Andrews won a majority of women, while Graham won about half of men. Trump's backing reportedly eroded support among independents and some Republicans worried about her inexperience and a possible "Graham family dynasty." Brent Chaplin, a voter who had always backed Republican candidates, voted for Andrews and said he hoped her win would be a "wake-up" call for Republicans.

Andrews campaigned for more than a year and won her primary outright before Lindsey Graham died, which forced her to adjust her strategy. She won the June 9 Democratic primary with 61.5 percent, well ahead of Brandon Brown at 30.2 percent and Kyle Freeman at 8.3 percent. In 2022 she ran in the state's 1st Congressional District against Rep. Nancy Mace and received about 42.5 percent. This time she ran on lowering healthcare costs, protecting access to care, affordability for working families and fighting corruption. She criticized Graham for supporting Republican-backed Medicaid cuts, for voting against efforts to end US involvement in the Iran war and for backing expanded data center development. Andrews called the war "illegal" and "unconstitutional" and pointed to its effect on gas prices.

Graham's campaign faced accusations that she was too closely aligned with Washington insiders and special interests, including insurance and artificial intelligence companies. Andrews also questioned her experience. In a debate over Taiwan policy, Graham made a remark about national security whose wording is reported two ways: "National security is not my thing" and "not that informed on national security." The only debate between the two candidates, held last month, covered the economy, the war with Iran, artificial intelligence and each candidate's claim that the other was unqualified. Former governors David Beasley, a Republican, and Jim Hodges, a Democrat, endorsed Andrews just over a week before the election. Outside groups also spent in the race, including $5 million from the Senate Leadership Fund in October and $827,000 from MAGA Inc in August.

Andrews' campaign was not free of controversy on her own side. LGBTQ+ advocates criticized an ad in which she referred to trans women as "biological men" and said she does not support gender surgery for minors, a shift from 2022, when she supported trans youth and criticized the "Save Women's Sports Act." Reports also say Trump used a transphobic slur against Andrews while campaigning for Graham.

Andrews held her victory party in Charleston. "You have shown the nation what is possible... that we will not bow down," she said. Graham addressed a subdued crowd in Columbia. "This is a tough cycle, and all of us need to be involved as we chart a path forward," she said.

Graham's brief tenure had itself been a first, as she became the first woman and the first graduate of a historically Black college or university to represent South Carolina in the Senate. Andrews' win comes nearly a century after Hattie Caraway of Arkansas became the first female US senator in 1932. As of October, 15 states, including Pennsylvania, Connecticut, New Jersey and Vermont, have never had a female US senator.