Leonora O'Reilly, the daughter of Irish immigrants, was born in New York City, the daughter of a printer and a garment worker, O'Reilly lost her father a year after her birth. She spent her childhood listening and watching her mother, Winifred Rooney O'Reilly, who taught her to appreciate how the labor movement could help women workers.
The family were poor and after a few years in school, she left to join her mother as a garment worker, taking a job in a collar factory at the age of eleven. Five years later she joined the Knights of Labor.
O'Reilly became active in trade union activities and eventually helped form a female chapter of the United Garment Workers of America. She also continued her academic education by attending the Brooklyn Pratt Institute. Later she taught at the Manhattan Trade School for Girls (1902-09).
O'Reilly was also involved in the formation of the Woman's Trade Union League. The main objective of the organization was to educate women about the advantages of trade union membership. It also support women's demands for better working conditions and helped to raise awareness about the exploitation of women workers.
The Woman's Trade Union League received support from the American Federation of Labour and attracted women concerned with women's suffrage as well as industrial workers wanting to improve their pay and conditions.
O'Reilly played a leading role in the garment workers dispute (1909-10) and led the investigation into the fire at the Triangle Shirtwaist Company that resulted in the death of 146 people. O'Reilly, who campaigned for woman suffrage and the Wage Earners' League and was active in the Henry Street Settlement House, was also a member of the Socialist Party of America and National Association for the Advancement of Colored People.