In addition to her medical achievements, Mayo participated in a number of other organisations. She was heavily involved in the University of Adelaide, serving on the university council from 1914 to 1960 (the first woman in Australia to be elected to such a position) and establishing a women's club and boarding college there. She was also the founder of the Adelaide Lyceum Club, an organisation for professional women. Mayo died on 13 November 1967, with the Medical Journal of Australia attributing the success of South Australia's infant welfare system to her efforts.
Helen Mary Mayo was born in Adelaide, Australia on 1 October 1878. She was the eldest of the seven children of George Gibbes Mayo (1845–1921), a civil engineer, and Henrietta Mary Mayo, née Donaldson, (1852–1930) and granddaughter of George Mayo, a prominent Adelaide doctor. Her formal education commenced at the age of 10, when she began receiving regular lessons with a tutor. At the age of 16, she was enrolled in the Advanced School for Girls on Grote Street (the forerunner of the Adelaide High School), from which she matriculated after one year, at the end of 1895.
Despite never having heard of female doctors, from an early age Mayo had been set on pursuing a career in medicine. However, Edward Rennie, then a professor at the University of Adelaide advised Helen's father that she was too young to commence study in Medicine, so in 1896, Mayo enrolled in the Faculty of Arts at the University of Adelaide. The death of her younger sister Olive at the end of her first year of study meant that Mayo was unable to sit her final exams for that year, and when she repeated her first year in 1897, she failed two of her five subjects (Latin and Greek). Having gained her father's permission, Mayo enrolled in medicine in 1898. She was a distinguished medicine student, coming top of her class and winning the Davis Thomas scholarship and the Everard Scholarship in her fourth and fifth years of study, respectively.
Upon her graduation at the end of 1902, Mayo took up a position as a resident medical officer at the Adelaide Hospital. In February 1904, she left for England to gain practical experience. There she worked as a clinical clerk at the Hospital for Sick Children in Great Ormond Street, London. To gain experience in midwifery, she went to Coombe Women's Hospital in Dublin, and after returning to London to complete a course in tropical medicine, she travelled to India where she worked for a year as a midwife in a Cambridge Mission to Delhi hospital for women and children. In 1906, Mayo returned to Adelaide and started a private practice in premises owned by her father on Morphett Street, next to the family home. With spare time on her hands, she began laboratory work at the Adelaide Hospital and took up an appointment as honorary anaesthetist at the Adelaide Children's Hospital.
In May 1909, Mayo presented a paper to an interstate conference on the subject of infant mortality. In it, she addressed the high infant mortality rate in South Australia, and claimed that more needed to be done to educate women for motherhood. Later that year, after hearing a talk about the success of a school for mothers in London, she and Harriet Stirling (the daughter of Edward Stirling) founded the School for Mothers in Adelaide. The Kindergarten Union made a room in its offices available for one afternoon a week, where a nurse would weigh babies and Mayo and Stirling would give advice. At the first annual meeting of the School a prominent medical doctor criticised the organisation for thinking that spinsters could teach mothers, who were guided by the "mother instinct" (both Mayo and Stirling were childless). In spite of this, the organisation flourished, and in 1911 a cottage in Wright Street was purchased and became the headquarters of the School. In 1927, the organisation became the Mothers' and Babies' Health Association (MBHA), and by 1932, it had branches throughout South Australia. Mayo's colleagues during this period included Dr. Marie Brown (1883–1949). Mayo served as the honorary medical officer of the association until her death in 1967, by which time the organisation gained a training school for maternal nurses and a hospital. In her honour, the Association inaugurated the annual Helen Mayo lecture. Eventually, in 1981, the Mothers' and Babies' Health Association was incorporated into the Department of Health of the South Australian Government.