Cancer nanomedicine is one of the most promising domains that has emerged in the continuing search for cancer diagnosis and treatment. The rapid development of nanomaterials and nanotechnology provide a vast array of materials for use in cancer nanomedicine. Among the various nanomaterials, covalent organic frameworks (COFs) are becoming an attractive class of upstarts owing to their high crystallinity, structural regularity, inherent porosity, extensive functionality, design flexibility, and good biocompatibility. In this comprehensive review, recent developments and key achievements of COFs are provided, including their structural design, synthesis methods, nanocrystallization, and functionalization strategies. Subsequently, a systematic overview of the potential oncotherapy applications achieved till date in the fast-growing field of COFs is provided with the aim to inspire further contributions and developments to this nascent but promising field. Finally, development opportunities, critical challenges, and some personal perspectives for COF-based cancer therapeutics are presented.