<p>Caleb Afendopolo, a prominent Karaite scholar of the 15th–16th centuries Byzantine-Ottoman realm, was a commentator, philosopher, and poet. A prolific author, he composed numerous works on Karaite principles of faith, halakhah, exegesis, philosophy, and sciences. He was a product of the Byzantine Greek-speaking Karaite society and a contemporary of the enormous wave of immigration in the Ottoman Empire of Jews expelled from the Iberian Peninsula who brought with them new intellectual trends that influenced his views and thought. His writings include fragments that contain anti-Christian polemics that have remained beyond the scope of scholarly research. Afendopolo’s polemical discourse addresses mainly heresiographic and legal issues based on historical arguments. His approach demonstrates a striking gap between a surprisingly positive image of the historical Jesus and fierce criticism of Christianity, encompassing some of its contemporary practices. The present study aims to reconstruct his perspective of Christianity in the context of major Rabbanite and especially Karaite polemical tendencies. For the first time, this article also presents fragments of anti-Christian polemics from Afendopolo’s works.</p>