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In 1802, McGuffey's family Moved to Tuscarawas Co., Ohio. He attended country school, and after receiving special instruction at Youngstown, he attended Old Stone Academy. Afterwards, he attended and graduated from Washington College, Pa, where he became an instructor.
He left Washington College in 1826 to become a professor at Miami University. While he was there, he wrote volumes one and two of his Mcguffey Readers. A year later in 1827, he was married to Harriet Spinning of Dayton, Ohio, with whom he had five children. In 1829, he was ordained at Bethel Chapel as a minister in the Presbyterian Church.
In 1836, he left Miami to become president of Cincinnati College where he also served as a distinguished teacher and lecturer. He left Cincinnati in 1839 to become President of Ohio University, which he left in 1843 to become president of Woodward College in Cincinnati.
In 1845, McGuffey moved to Charlottesville, Virginia where he became Professor of Philosophy at the University of Virginia. A year after his first wife Harriet died in 1850, he married Miss Laura Howard, daughter of Dean Howard of the University of Virginia, in 1851. McGuffey is buried at university burying ground, in Charlottesville, Virginia.