Velma Barfield was born in Eastover, North Carolina, and grew up near Fayetteville. It was reported that her father was physically abusive, and her mother, Lillian Bullard, did not step in to protect her. In 1949, seeking to escape her difficult home life, Barfield married Thomas Burke. 

They had two children and were said to be happy until Barfield underwent a hysterectomy and began experiencing back pain. These health issues contributed to significant changes in her behavior and eventually led to her developing a drug addiction.

Burke's drinking habits led to escalating arguments with Barfield. On April 4, 1969, after Burke had passed out, Barfield and her children left the house. Upon their return, they found the house burned down and Burke dead. In 1970, Barfield married Jennings Barfield, who died of heart complications less than a year later, on March 22, 1971.

In 1974, Barfield's mother, Lillian Bullard, experienced severe diarrhea, vomiting, and nausea, but recovered after a few days. During the Christmas season that same year, Bullard fell ill again with the same symptoms and died in the hospital on December 30, 1974. In 1975, Barfield was convicted of writing bad checks and was sentenced to six months in prison, serving three months before her release.

Barfield began working as a caretaker for the elderly in 1976, looking after Montgomery and Dollie Edwards in Lumberton, North Carolina. Montgomery fell ill and died on January 29, 1977. Just over a month later, Dollie exhibited the same symptoms and died on March 1. Barfield later confessed to Dollie Edwards' murder. In 1977, Barfield took a caretaker job for Record Lee, who had a broken leg. On June 4, 1977, Record's husband, John Henry, experienced severe stomach and chest pains along with vomiting and diarrhea. He died soon after, and Barfield confessed to his murder.

Another victim, Rowland Stuart Taylor, was Barfield's boyfriend and a relative of Dollie Edwards. Fearing he had discovered her check forgery, Barfield poisoned his beer and tea with arsenic-based rat poison. Taylor died on February 3, 1978, and an autopsy revealed arsenic in his system. After Barfield's arrest, Jennings Barfield's body was exhumed and found to have traces of arsenic, a murder she denied committing. Although she confessed to the murders of Lillian Bullard, Dollie Edwards, and John Henry Lee, she was only tried and convicted for Taylor's murder.

Jonathan Byrd, singer-songwriter and grandson of Jennings Barfield, referenced the murders in his song "Velma" from the album Wildflowers. Barfield was imprisoned at Central Prison in Raleigh, North Carolina, in an area designated for escape-prone and mentally ill prisoners, as there was no specific area for women under death sentences at the time. She was the only female death row inmate in the state. A death row unit for female inmates was later established at the North Carolina Correctional Institution for Women.

During her time on death row, Barfield became a devout Christian and spent her last years ministering to prisoners, receiving praise from Billy Graham for her efforts. There was an attempt to commute her sentence to life imprisonment due to her Christian ministry involvement.

Dorothy Otnow Lewis, a Professor of Psychiatry at New York University, testified that Barfield suffered from dissociative identity disorder, claiming that Barfield's other personality, "Billy," had killed her abusers. The judge dismissed this testimony, saying, "One of them did it, I don't care which one."

After her appeal was denied in federal court, Barfield instructed her attorneys not to pursue a further appeal to the U.S. Supreme Court. She was executed on November 2, 1984, at Central Prison. Before her execution, she expressed remorse and gratitude to her supporters. For her last meal, Barfield chose Cheez Doodles and Coca-Cola. She was buried in a small, rural North Carolina cemetery near her first husband, Thomas Burke. Barfield's execution sparked political controversy when Governor Jim Hunt, who was running for a U.S. Senate seat, denied her clemency request.