William Holmes McGuffey was born on September 23, 1800 in Washington, Pennsylvania. His parents, Alexander and Anna (Holmes) McGuffey, were farmers who taught their son as a young boy. In 1826, McGuffey married Harriet Spinning, with whom he had five children. Harriet died in 1850, and William McGuffey married Laura Howard, with whom he had one child.

McGuffey began his education at Old Stone Academy in Darlington, Pennsylvania. He then went on to get his AB from Washington College in Washington, Pennsylvania. Although he did not get that degree until September of 1826, he was already teaching ancient languages at Miami University in Oxford, Ohio. While teaching, McGuffey also became a minister of the Presbyterian Church.

McGuffey made a deal with publishers Truman and Smith to write four readers that were directed toward young boys and graded them on their reading. These books not only helped the boys with reading, but contained messages about social, moral, and religious issues. They were called the Eclectic Readers to show the breadth of the educational theory behind them. These educational books are still used today.

McGuffey held the position of president at Cincinnati College and at the Ohio University of Athens. He was also active in the Western Literary Institute. Approximately 122,000,000 copies of McGuffey's Eclectic Readers were sold and were the most influential educational resource for Americans in the late nineteenth and early twentieth centuries.

William McGuffey died on May 4, 1873, in Charlottesville, Virginia, where he had been Professor of Moral Philosophy since 1845.