Thomasius published only one natural philosophical treatise, the Versuch vom Wesen des Geistes (Essay on the Nature of Spirit) of 1699, a work in which he described the Cartesians’ mechanistic interpretation of nature as pagan and impious, and as a reflection of sinful pride in the powers of the human intellect. According to Thomasius, Cartesianism and orthodox Lutheranism shared one critical defect, however different they were in other respects: both placed too much emphasis on the intellect. They ignored the importance of the will-as-desire in their view of human nature and failed to recognize the need for a reform of the heart to acquire religious faith, virtue, and thus wisdom.

Cartesianism in a strict sense was very rare at German universities around 1700, but Thomasius was responding to a loosely Cartesian form of natural philosophy, which had established itself in the medical faculty of Halle, and which was represented especially by physicians such as Friedrich Hoffmann (1660–1742), whose so-called “iatro-mechanistic” theory of medicine treated the human body as a machine, composed of particles of inert, extended matter, whose movements were directed by the soul. Hoffmann's ideas reflected the influence of physicians such as Hermann Boerhaave (1668–1738) in Leiden and Giovanni Borelli (1608–79), who interpreted diseases as the mechanical malfunctioning of this body-machine. Hoffmann's theory did not rest on the same neo- Platonic metaphysical foundation as Descartes’ physics, but it was not uncommon for Cartesian physics to be used without Descartes’ metaphysics. Similarly, in the Versuch, Thomasius did not examine Descartes’ metaphysics, but only the Cartesian definition of bodily entities as no more than passive, extended matter.

Thomasius's own natural philosophy was hermetic and quasi-mystical. It explained natural phenomena as due to the operation of hidden forces of sympathy and antipathy, that is, attraction and repulsion, between material bodies. These ideas were closer to the theories of thinkers like Paracelsus (1493–1541) than to those of the figures that are more commonly associated with the Scientific Revolution and the Enlightenment, such as Robert Boyle or Isaac Newton. It is not surprising, then, that Thomasius's natural philosophy is often considered a curiosity, which is marginal to his main, “enlightened” philosophical interests, as an aberration in his personal intellectual history, and a work that is of little consequence to his later thought.