He was born the son of Alexander and Anna (Holmes) McGuffey near Claysville in Washington County, Pennsylvania, which is 45 miles southwest of Pittsburgh. In 1802 the McGuffey family moved further out into the frontier at Tuscarawas County, Ohio. He attended country school, and after receiving special instruction at Youngstown, he attended Greersburg Academy in Darlington, Pennsylvania. Afterwards, he attended and graduated from Pennsylvania's Washington College, where he became an instructor.

He was close friends with Washington College's President Andrew Wylie and lived in Wylie's house for a time; they often would walk the 3 miles to Washington College together.

McGuffey left Washington College in 1826 to become a professor at Miami University in Oxford, Ohio. 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. It was in Oxford that he created the most important contribution of his life: The McGuffey Readers. His books sold over 122 million copies. He was very fond of teaching and children as he geared the books toward a younger audience.

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 the 4th president of Ohio University, which he left in 1843 to become president of Woodward College (really a secondary school) 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 in the university burial ground, in Charlottesville, Virginia. The School of Education at Miami University is housed in McGuffey Hall which is named for him and his home in Oxford is a National Historic Landmark offering tours on weekdays.

McGuffey is credited with the following quotation:

"The christian religion, is the religion of our country. From it are derived our prevalent notions of the character of God, the great moral governor of the universe. On its doctrines are founded the peculiarities of our free institutions."

The McGuffey School District in Washington County, Pennsylvania is named for William Holmes McGuffey. The industrialist Henry Ford cited McGuffey Readers as one of his most important childhood influences. In 1934 he had the log cabin where McGuffey was born moved to Greenfield Village, Ford's museum of Americana at Dearborn, Michigan.

McGuffey awards

Named for William Holmes McGuffey's influential primers that first appeared in 1836 and remained in print until 1921, the McGuffey longevity awards recognize long-lived, still-in-use textbooks of excellence.