Samuel Henderson was born in Jefferson County, Tennessee, on March 12, 1817, to John F. and Nancy (Mohler) Henderson. The family moved to Talladega County, Alabama, where his father established a printing office and published The Southern Register and Talladega Advertiser in 1835. It was there that Henderson learned the printing and publishing trade. At fifteen, Henderson united with the church. He married Eliza W. McGehee in January 1840.
Ordained to the ministry in 1840, Henderson became the pastor of First Baptist Church of Talladega but moved to First Baptist Church of Tuskegee in 1846, serving there for more than twenty years. Three of his church members bought the South Western Baptist in 1852 and convinced their pastor to edit the religious newspaper. They bought a press with equipment and moved the operation to Tuskegee. By 1859, with his brother-in-law, Hardin E. Taliaferro, serving as co-editor, Henderson felt he could resign. In 1861 he was elected a delegate to the 1861 Secession Convention.
Taliaferro held the editorial reins until 1862, but when he resigned as editor and owner, Henderson returned to the paper while still serving the Tuskegee church.
Through the war years, Henderson filled the columns with his strong Southern editorials, denominational news and war reports, a move that resulted in Federal troops in Tuskegee shutting down the press in April 1865. Henderson remained quiet only until he could partner with James Toon, owner of the Christian Index of Georgia. In 1865, he and Toon joined the Georgia and Alabama papers to form the Christian Index and the South-Western Baptist. Henderson would serve as editor of the Alabama Department of the paper until he retired in December 1866.
He continued pastoring churches in Alabama and served as president of the Alabama Baptist Convention from 1868 to 1873. He retired to his farm in Shelby County in 1889. Henderson died in Troy on February 16, 1890, and was buried in Oak Hill Cemetery in Talladega, leaving his wife, three sons and two daughters behind. He was remembered as a pastor, writer, printer and editor faithful to Alabama Baptists.