Sanford rose in the ranks of local and national educators, becoming principal and superintendent of schools in Chester County, Pennsylvania.
Dr. William Watts Folwell, President of the University of Minnesota at the time, invited Sanford to join the faculty.
During her tenure at the university (1880–1909) Sanford was a professor of rhetoric and elocution, and she lectured on literature and art history.
Sanford made strong connections with her students and challenged them with surprise tests and poetry recitations.
She held student social events in her Como neighborhood home and gave speeches to organizations and groups across the nation.
Sanford became head director for Northwestern Hospital, and created and served as president of the Minneapolis Improvement League.
Her address to a 1916 Minneapolis convocation honoring her was headlined as "Trumpet of Social Reform is Sounded by Maria Sanford.
She was the namesake of a World War II Liberty ship, the SS Maria Sanford, launched in 1943.