During the sixteenth century, Jesuit renovations of medieval Aristotelian conceptions of the soul afforded an important discursive field for René Descartes to craft a notion of the soul as a substance distinct from the body and defined by thought. Cartesianism, however, augmented rather than diminished the skeptical crisis over the soul and the mind–body union. This article explores the work of a Jesuit intellectual, René-Joseph Tournemine, whose attempt to navigate between Malebranche’s Cartesianism and the metaphysics of Leibniz proved influential during the eighteenth century in ways that intersect with the development of Enlightenment biological science. Tournemine’s theologically motivated conjectures about the nature of the mind–body union reinforced an important shift away from considering the soul as a metaphysical substance in favor of seeing it as a pervasive motive force or vital principle animating the human organism.