The Colloquies on the simples and drugs of India (1563) were conceived and published at a sensitive moment, both in terms of the history of print culture and of European geographical expansion. They represented the culmination of a life-time project for their author Garcia de Orta who had lived for almost thirty years in Portuguese Goa. Although the importance of the work in sixteenth-century natural history and medicine has been generally acknowledged in Portuguese and international historiography, there are very few recent, detailed studies of the book informed by new approaches. This paper presents an integrated analysis of Orta’s Colloquies as a literary, medical and cultural text. It aims to reveal not only the rich and subtle dynamics of the work but also to contribute to a better understanding of Orta’s legitimation strategies as an author in a sixteenth-century world reconfigured by the new opportunities of the printing press, geographical expansion and increased material and cultural mobility.