[citation needed] In 1813 he married Margaret Ritchie, daughter of Craig Richie,[3] a wealthy Canonsburg merchant.

He was close friends with William Holmes McGuffey, who lived in Wylie's house for a time; they often would walk the 3 miles to Washington College together.

[6] In 1828, the trustees of the newly formed Indiana College wrote to Wylie offering him the position of president.

In 1837 he recruited his half-cousin Theophilus Adam Wylie to Indiana College to teach mathematics, natural philosophy and chemistry.

He guided the school through an important time of transition as the state legislature rechartered the college as Indiana University in 1838.

Wylie and his wife Margaret (who was born in 1791 and died in 1859) had twelve children: Andrew Jr., William, Mary Ann, Craig Ritchie, Elizabeth, John Hosea, Samuel, Margaret, Irene Catherine, Redick McKee, Anderson McElroy, Jane Melheme.