Henderson is famous for a definition of nursing: "The unique function of the nurse is to assist the individual, sick or well, in the performance of those activities contributing to health or its recovery (or to peaceful death) that he would perform unaided if he had the necessary strength, will or knowledge" (first published in Henderson & Nite 1978, p. 5, 1955 ed.). She is known as "the first lady of nursing" and has been called, "arguably the most famous nurse of the 20th century" and "the quintessential nurse of the twentieth century". In a 1996 article in the Journal of Advanced Nursing Edward Halloran wrote, "Virginia Henderson's written works will be viewed as the 20th century equivalent of those of the founder of modern nursing, Florence Nightingale."
Henderson was born on November 30, 1897 in Kansas City, Missouri to Daniel B. Henderson, a lawyer who worked with Native Americans, and Lucy Minor (Abbot) Henderson. She was the fifth of their eight children. She grew up in Virginia where she received her early education at her grandfather's community boys' school.