She went on to earn a Master's in Philosophy at Columbia University in New York. Holmes devoted her energies to teaching academic, or college preparatory, curriculum at the high school level for more than thirty years, mostly in Chicago, Illinois. She was voted "Best Latin Teacher" in the entire city. There Holmes distinguished herself further by leading the history department at Du Sable High School for several years, an unusual leadership role for any woman in those times.
In addition, Holmes served as president and vice-president of the Theta Omega chapter of Alpha Kappa Alpha in Chicago, where she was active for more than 30 years in programs for education and health. She also was active with the NAACP and the YWCA. Margaret Holmes demonstrated in her work as an educator and civic activist how African American sororities supported women "to create spheres of influence, authority and power within institutions that traditionally have allowed African Americans and women little formal authority and real power.
For nine years, Margaret served as a history, Latin and English teacher at the same Baltimore high school as fellow founder Lucy Diggs Slowe. By studying during summers, Flagg earned a Master of Arts degree in philosophy in 1917 from Columbia University in New York.
On August 1, 1917, Margaret married John Clay Holmes. The couple moved to Chicago, Illinois, where Margaret returned to teaching in 1922. She first taught Latin at Wendell Phillips High School, the first secondary school for African Americans in Chicago. It attracted talented teachers and students. Holmes earned recognition as "Best Latin Teacher of the City" by the North Central Association.
As the school expanded, it was renamed Du Sable High School. Margaret Holmes headed the history department for several years, until 1931. Such a position of leadership at the high school level was unusual for women educators of the time. Holmes was an educator for more than 30 years, until 1953, teaching generations of students.
For more than thirty years, from 1922 to 1953, Margaret Holmes was active in Chicago's Theta Omega alumnae chapter of Alpha Kappa Alpha. She served as the vice-president and president of the chapter. Both the chapter and national organization raised funds in the 1920s and 1930s for scholarships, and contributed to the NAACP and Urban League. They worked to support education for African Americans and gain civil rights. Holmes helped serve the African American community through challenges of the Great Depression and the Great Migration, when Southern blacks arrived in Chicago at the rate of 5,000 per week.
After her move later in life to New York, Holmes became a member of the Tau Omega chapter of Alpha Kappa Alpha. In total, she worked with the sorority nearly seventy years to build social capital.
With her husband John, Margaret traveled across the United States and Canada. In Paris, France, Margaret met the famous African American dancer Josephine Baker. The Holmes couple were received by Pope Pius XI in 1931. After her husband died in 1946, Margaret Holmes moved to New York City to live with her sister. Holmes died on January 29, 1976.