Avicenna’s Canon of Medicine enjoyed great popularity not only among physicians, but also among philosophers. The first book on Generalities (Kull?y?t) in particular proved so popular that many commentaries, supercommentaries and abridgements on it were produced from the eleventh century onwards. Yet, the third book, discussing so-called ‘topical diseases’—diseases affecting a particular part of the body such as the eye, the ear and so on—contains much philosophically relevant discussions, especially in the sections on the brain. There are only a few commentaries on this book of the Canon, two of which are by Ibn al-Naf?s (d. 1288) and Ibn al-Quff (d. 1286). In this paper, I shall offer a first analysis of the sections on melancholy. Melancholy was generally defined as an impairment of reason without fever and caused by black bile. There is a long tradition of Arabic medical texts on melancholy, reaching back to the translations of key works by Rufus of Ephesus (flourished first century) and Galen of Pergamum (d. ca. 216). Avicenna’s own chapter on melancholy in the Canon draws heavily on Paul of Aegina (d. ca. 690). The two commentators discussed here, Ibn al-Naf?s and Ibn al-Quff, approached this topic from different angles, although they share some exegetical strategies. I shall contrast their approach in their Canon commentaries with that in their commentaries on the Hippocratic Aphorisms. In this way, I shall offer a first vignette on how two powerful intellectuals interpreted Avicenna’s account of melancholy and relate it to their other exegetical practices.