Leon was also an active man who taught at the University of Salamanca, translated classical and biblical literature, and wrote on religious themes. Twice denounced before the Inquisition, he was imprisoned for "heresy," though he returned to the University to later hold the chairs of Moral Philosophy and Biblical Studies. Tradition has it that he began his lecture the first day after returning from four years' imprisonment with the words "As we were saying yesterday...."

The mysticism of his poems, contends translator Willis Barnstone, has not been adequately appreciated because critics have been distracted by Leon's other achievements and battles and because they have worked with too narrow a definition of mysticism.

In his introduction Barnstone compares Leon with other Spanish mystical poets and explains the Christian, Judaic, and Islamic influences on Spanish mysticism. He discusses the varieties of mystical experience and provides the context for understanding Leon's mysticism, concluding, "Who is Luis de Leon? Look at the poems. He is there."