Bishop DuBose gained notability as an author, editor, and a leader in the American temperance movement.
Then transferring back to Mississippi, he was appointed Pastor of First Methodist Church, Jackson (1896–98).
DuBose was elected Secretary of the Epworth League, serving the Church in this capacity for the next twelve years, insisting that the General Conference not re-elect him to that office.
He then transferred to the North Georgia Annual Conference where he was appointed Pastor of St. John's Church in Augusta (1910–12).
Dr. Horace Mellard DuBose was elected to the office of Bishop and consecrated as such at the 1918 General Conference of the Methodist Episcopal Church, South.
Noting his importance as a temperance leader, upon his death Time magazine quoted him as having said in 1932, "If the Angel Gabriel should come down and tell me that he had changed his mind on prohibition and wanted it resubmitted, I would not follow him."