On July 7, 1878, Francis was ordained as a Presbyterian minister. He would spend over fifty years in the pulpit, most of it at Washington's 15th Street Presbyterian Church. He was noted as one of the most articulate opponents of racism: "Race prejudice can't be talked down, it must be lived down."
When Henry Grimké died in 1852, his will freed Francis and placed him under the guardianship of his white half-brother, Montague. Eight years later, when Montague threatened to enslave Francis, who was now ten years old, he fled and served as valet to a Confederate officer. When Grimké visited Charleston some months later, Montague seized and imprisoned him. Francis became ill and would have died had his mother not been allowed to nurse him. Before he was completely well again, his brother Montague sold him to another officer. But at the end of the war, Francis was emancipated with other African-Americans.