It was 1976 when Lindsey Graham and his sister lost their mother to cancer. Just 15 months later, their father died of a heart attack.

Mr. Graham was 22. His sister was just 13. Darline Graham Nordone said over the years that on the day their father died, she stood terrified of what it meant to be an orphan.

She recalled Mr. Graham running to grab her, pulling her in for a hug.

“He was like ‘I am so sorry, but it’s going to be OK. I’m going to take care of you,’” Ms. Nordone said in a recent video recollecting the moment. “And he did. He’s always been there for me.”

The bond between brother and sister became particularly public as Mr. Graham, who never married or had children of his own, grew into a national political figure. She introduced him as he launched a run for the White House and vouched for him as a man of integrity who could help his constituents as he had long helped her.

When a tabloid once asked Mr. Graham who would serve as his first lady should he win the presidency, he joked — or maybe half-joked — that his sister could fill the role.

The two grew up in a small room behind the Sanitary Cafe, an establishment on Main Street in Central, S.C., that their parents operated as a bar, liquor store and pool hall. Ms. Nordone recalled that even when their parents were alive, she ran to her brother when she was sick or needed help with homework. He taught her how to ride a bicycle, pushing it and then running beside shouting encouragement. He cared for her when she fell.

“He’s kind of like a brother, a father and a mother rolled into one,” she said in a 2015 interview with The New York Times. Ms. Nordone declined an interview Sunday, saying the loss of her brother, who died Saturday after what his office described as a “brief and sudden illness,” was still too raw.

After the deaths of their parents, Ms. Nordone moved in with an aunt and uncle as Mr. Graham continued his studies at the University of South Carolina. While other students would stay on campus having fun on the weekends, she once recalled, Mr. Graham would travel back to care for her.

He enlisted in the Air Force and became his sister’s legal guardian, allowing her to qualify for his military benefits. She credited him for making sure she finished high school and went to college.

Ms. Nordone went on to become a mother of two who worked to help people with disabilities find jobs. Mr. Graham took particular pride in her success.

“Of all the things that have happened in my life, her turning out so well is the highlight of it by far,” he told C-SPAN in 2015.

Over the years, political opponents, particularly in South Carolina, had taunted Mr. Graham for his bachelor status, some speculating that he was gay, something he denied. Mr. Graham had suggested that the way his life played out led him to never marry. Ms. Nordone once said it had been hard for her to watch the personal attacks against her brother, and she said his role in caring for her as one of the reasons that he had not married.

“He was a young man taking on a young girl and teenager to raise,” she said. “He was just dedicating all of that time to raising me and going to school and trying to get an education. There’s just only so much time in a day.”

Bob McAlister, a former adviser to Mr. Graham, described the bond he had with his sister as extraordinary and that his decision to step up and serve as her guardian “personifies who he was.”

“I can’t stress his loyalty to his sister and his family, and that’s something that most people don’t understand,” he said.

Emily Cochrane contributed reporting.