This study analyses the autos sacramentales, or Eucharistic plays, by Sor Juana Inés de la Cruz (1651–95). It focusses on their relationship to the changing currents of philosophical thought in the late-seventeenth century Hispanic world, from a mindset characterized by scepticism, Neostoicism, and suspicion of the material world as a source of truth, to an empirical approach to the natural world that understood the information received by the senses as a fallible, yet useful, provisional source of knowledge. By examining each play in turn, along with the introductory loa with which they were intended to be performed, the study explores how each drama seeks to integrate empirical ideas with a Catholic understanding of transubstantiation. At the same time, each individual study identifies new sources for these plays, and demonstrates how these illuminate, or nuance, present readings of the works. The study of El divino Narciso employs a previously little-known source to illuminate its Christological readings, as well as Sor Juana’s engagement with notions of wit and conceptism. The analysis of El cetro de José explores her presentation of different approaches to perception to emphasize the importance of both the material and the transcendent in understanding the sacraments. The final section, on San Hermenegildo, explores the influence of the Christianized stoicism of Justus Lipsius, and demonstrates how Sor Juana used this work to attempt her most ambitious reconciliation of an empirical approach to the material world with a Neostoic approach to Christian morality and orthodox Catholic sacramental theology.