Simonton was born in present-day West Hanover Township, Pennsylvania, and spent his childhood on the family's estate, named Antigua.

The boys, William, John, James, Thomas and Ashbel, called themselves the "quinque fratres" (five brothers).

Disappointed with the lack of attention by the local authorities for teaching, Simonton went back to Pennsylvania and tried to become a lawyer, although by that time many people would advise him to become a minister, something to which his mother had consecrated him at his birth.

In his first term, he heard in the seminary's chapel a sermon by Charles Hodge, one of his teachers, which moved him to the missionary work in foreign lands.

On January 12, 1862, soon after organizing the Presbyterian church in Brazil, Simonton vacationed in the United States, where he married Helen Murdoch, in Baltimore.