She graduated with a Master of Arts in classics in 1886 and took up an immediate career in education by providing lectures and private lessons for students of College Hall.

[4] Macdonald was chosen from a field of 65 applicants to be the founding principal of the Women's College at the University of Sydney, and took up her position in rented premises at 'Strathmore' in Glebe in March 1892, with four students.

[2][5] Macdonald worked tirelessly to establish prosperity for the college, both economically and culturally, at a time when women's education was a low priority and in limited demand.

[1] Aided by her lifelong friend and companion, Evelyn Dickinson, Macdonald sought to establish a strong foundation for supporting women's education, based on values of social and intellectual equality.

[1] The architecture and grounds of the college reflected Macdonald's belief that gracious surroundings were an essential part of a liberal education.