He was a student for about six years at the University of Seville studying Dialectics and Philosophy, where he was influenced by the sermons of Giles of Viterbo amongst others.

In spite of the dangers, twelve of them fled to Geneva, including Casiodoro de Reina and Antonio del Corro as well as Valera himself.

In that same year, Valera was made a professor of Theology at the University of Cambridge and became a Fellow of Magdalene College, where his compatriot Francisco de Enzinas had held a fellowship before Marian persecutions.

Most famously, however, over a twenty-year period Valera amended Reina's 1569 translation of the Bible into the Spanish vernacular and travelled to Leiden in 1602 with a printer to present the first copy to Maurice of Nassau and the States General of the Netherlands, from where it was published.

In response to these various works, Valera was listed in the Index Librorum Prohibitorum and called "el hereje español" ("the Spanish heretic") par excellence.