From about 1495 to 1509 he occupied the chair of natural philosophy until the closing of the schools of Padua, when he took a professorship at Ferrara where he lectured on the Aristotle's De Anima (On the Soul) and entelechy.

The predominance of medical science at Padua had cramped his energies, but at Ferrara, and even more at Bologna, the study of psychology and theological speculation were more important.

In 1516 he produced his great work De immortalitate animae (On the Immortality of the Soul), which gave rise to a storm of controversy between the orthodox Thomists of the Catholic Church, the Averroists headed by Agostino Nifo, and the so-called Alexandrist School.

Pomponazzi claimed the right to study Aristotle for himself, and devoted himself to the De Anima with the view of showing that Thomas Aquinas had entirely misconceived the Aristotelian theory of the active and the passive intellect.

(This debate influenced his 1591-1631 successor in the chair Cesare Cremonini, whose adherence to Aristotle led to the opposite conclusion of the mortality of the soul.)