One of the less well-researched areas in the recent renaissance of the study of Reformed orthodoxy is anthropology. In this contribution, we investigate a core topic of Reformed orthodox theological anthropology, viz. its treatment of the human being as created in the image of God. First, we analyze the locus of the imago Dei in the Leiden Synopsis Purioris Theologiae (1625). Second, we highlight some shifts of emphasis in Reformed orthodox treatments of this topic in response to the budding Cartesianism. In particular, the close proximity of the unfallen human being and God was carefully delineated as a result of Descartes’s positing of a univocal correspondence between God and man; and the Cartesian suggestion that original righteousness functioned as a barrier for certain natural impulses, was rejected. Third, we show how, in response to the denial of this connection, the image of God was explicitly related to the concept of natural law. Tying in with similar findings on other loci, we conclude that Reformed orthodox thought on the imago Dei exhibits a variegated pattern of extensions, qualifications, and adjustments of earlier accounts within a clearly discernable overall continuity.