When Sor Juana Inés de la Cruz (1648?-1695) famously described the natural secrets of cooking, she invoked some of the foundational terms of colonial science and society, from Aristotelian paradigms to Columbian acts of claiming. Scholars have long noted the importance of scientific knowledge to Sor Juana and underscore her engagement with Indigenous cultures, languages, and traditions. But few scholars have examined the intersection of Indigenous knowledge and scientific writing in Sor Juana’s ouvre. This chapter, grounded in a reading of classical natural philosophy, as it was expressed in Sor Juana’s Respuesta (1695), represents an effort to bring these research areas into dialogue. By juxtaposing Mayan-language documents from colonial Yucatán with Sor Juana’s masterful defense of knowledge in central New Spain, this chapter analyzes how Indigenous ways of knowing may have shaped one of the most important treatises on knowledge in colonial Mexico, thus suggesting. ways in which colonial letters both mark and help to promote critical transitions in the meaning of knowledge, epistemological categories, and the nature of knowledge production itself.