The next year, in 1811, Wylie was elected unanimously to serve as president of Jefferson College. He was licensed to preach in 1812, and in 1813 was ordained as a Presbyterian Minister. In 1813 he married Margaret Ritchie, daughter of a wealthy Canonsburg merchant.
He guided the school through an important time of transition as the state legislature rechartered the college as Indiana University in 1838.
1842 Wylie established the law department at Indiana University, which became the School of Law in 1889.
In Bloomington, Wylie continued to have conflicts with Presbyterians over Calvinist theology. In 1841, he left the Presbyterian Church to become a deacon in the Protestant Episcopal Church, and became an ordained priest in 1842.
Wylie died in office in 1851 from an illness.
During his time as president at Indiana University, enrollment raised from 40 to 74 enrolled in the college, 58 in the preparatory department, and 28 in the law department.