After having edited the Boston Recorder for several years, he taught Greek at Dartmouth College from 1831 to 1833 and sacred literature at Lane Theological Seminary in Cincinnati, Ohio from 1830 to 1840. While in Cincinnati, Stowe became an important advocate for the development of public schools in the western US. He was critical in the establishment of the College of Teachers there in 1833. Additionally, his 1836 Report on Elementary Instruction in Europe urged Ohio to adopt a state-backed educational system like Prussia's. The Ohio State Legislature ordered a copy of the book for each of the state's 8,500 school districts and more copies were given to other state legislatures. Also, he married his wife, Harriet, in 1836.
He taught religion at Bowdoin from 1850 to 1852 and at Andover Theological Seminary from 1852 to 1864. While at Bowdoin, Harriet began writing her soon-to-be-acclaimed novel, Uncle Tom's Cabin (1854). After the novel became world-known, Calvin wrote his own best-selling book, Origin and History of the Books of the Bible (1867), one of the first books to examine the bible from an historical perspective.
His childhood stories served as the basis for Harriet's books, Oldtown Folks (1869) and Sam Lawson's Old Fireside Stories (1872).