In 1900 she began her career in social reform by urging the establishment of a settlement house near the impoverished rural town of Proctor, Kentucky. In the same year, she helped found the Women's Emergency Committee (later reorganized as the Lexington Civic League). The league agitated successfully for the establishment of playgrounds and kindergartens in poorer districts of the city and for legislation setting up a juvenile court system, regulating child labour, and compelling school attendance. Also in 1900 Breckinridge led in founding the Lexington Associated Charities, which organized community charity along modern casework lines.

Plagued by tuberculosis, Breckinridge from 1905 was active in local, county, and state tuberculosis societies. She helped secure establishment of the state Tuberculosis Commission in 1912 and served as its vice president until 1916, in which year her fund-raising campaign culminated in the opening of the Blue Grass (later the Julius Marks) Sanatorium in Lexington. In 1906 she was appointed to the State Federation of Women's Clubs, and working through that body she campaigned successfully for legislation granting women the vote in school elections. From 1912 to 1915 and again from 1919 to her death, Breckinridge was president of the Kentucky Equal Rights Association, which worked to secure legislation recognizing the rights of married women to enjoy their own earnings, to make wills, and to be equal guardians of their children, as well as legislation limiting working hours for women and providing for women physicians in state mental hospitals, among other reforms. In 1913–15 she was a vice president of the National American Woman Suffrage Association, on whose behalf she traveled and spoke widely, demonstrating a remarkable gift for oratory. The ratification of the Nineteenth Amendment by the Kentucky legislature in January 1920 was largely credited to her efforts. In 1920 she undertook an extensive campaign tour on behalf of the League of Nations and the Democratic Party.