Covalent organic frameworks (COFs) are emerging crystalline porous materials composed of covalently linked and periodically arranged organic molecules, which exhibit mechanical properties mediated by structural diversity. Meanwhile, the tunable mechanical properties of COFs have been widely applied in drug delivery and cancer therapy. Herein, we first summarize the regulation strategies of COFs with different mechanical strengths, such as structural dimensions, pore sizes, and host-guest interaction forces. Then, the remarkable achievements of COFs with different mechanical properties in drug delivery and cancer therapy in recent years are introduced. Finally, the mechanical strength regulation of COFs and the remaining challenges for biomedical applications are presented. This review provides a more comprehensive understanding of the application of COFs systems with tunable mechanical properties in the field of biomedicine, and promotes the development of interdisciplinary research between COFs materials and nanomedicine.