At the age of three, her family moved in search of improved educational opportunities, to Maryland, where her father purchased a small farm to provide for his family. During those early days, the Pettigens were poor but were rich in aspirations for their children, instilling in them the conviction that it was possible to succeed at any task if one worked hard and persevered.

Upon completing her public education in segregated schools and finding no first rate college in Maryland which admitted Blacks, McMillan enrolled at Howard University in Washington, D.C.  She commuted  to school for four years because she was unable to pay the cost of board and lodging. A scholarship awarded to her by the Epsilon Chapter of Alpha Kappa Alpha Sorority - the first one so awarded - helped finance her undergraduate training. In 1926, she received a Bachelor of Arts degree in education and immediately began her teaching career.

As the years passed, she became interested in advanced training but found that most local graduate schools were closed to Blacks. She commuted to Columbia University, and while studying there she began to seriously question the inequities in the Maryland public education system and decided that this issue would be the foundation of her master's thesis. Her thesis, entitled "Factors Affecting Secondary Education in the Counties in Maryland," furnished a basis for attacks on Maryland's racist dual school system with its unequal school terms, salary scales, curricula, etc. This thesis had far-reaching consequences. On the one hand, her efforts to effect change resulted in her election as President of the Maryland State Colored Teachers' Association and as Regional Vice-President of the National Association of Colored Teachers. On the other hand, her professional career suffered greatly, resulting in McMillan being denied the promotions she deserved in the Baltimore City School System.

In 1969, one year after retiring from the Baltimore City Public Schools, she assumed the presidency of the Baltimore Branch of the National Association for the Advancement of Colored People (NAACP). The NAACP was established in 1909 in response to the mounting tide of legalized racism. From its inception, it was the primary voice and chief proponent of human equality for Black Americans. In 1976, the National Office was threatened with bankruptcy as a result of a suit levied against it in connection with a 1966 boycott of white merchants in Port Bigson, Mississippi. McMillan led the fight in Maryland by launching a fundraising drive to help defray expenses. Her efforts resulted in the Baltimore Branch raising the largest local contribution.

In 1984, McMillan was elected national president of the 400,000 plus-member NAACP, a position she held until just recently. She feels that although many good laws have been passed, "The NAACP must appeal to the young people of today and make them aware of what young people were able to do before, and show them exactly how much of what has been done is being undone." She continues her work in education as a member of the Board of Regents of Morgan State University and has served many other groups and received numerous awards and citations for her activities.