Covalent organic frameworks (COFs) are constructed exclusively with lightweight organic scaffolds, which can have a 2D or 3D architecture. The ease of synthesis, robust skeleton and tunable properties of COFs make them superior candidates among their counterparts for a wide range of uses including biomedical applications. In the biomedical field, drug delivery or photodynamic-photothermal (PDT-PTT) therapy can be individually considered a potential parameter to be investigated. Therefore, this comprehensive review is focused on drug delivery using COFs, highlighting the encapsulation and decapsulation of drugs by COF scaffolds and their delivery in biological media including live cells. Versatile COF scaffolds together with the delivery of several drug molecules are considered. We attempted to incorporate the status of drug encapsulation and decapsulation considering a wide range of recent publications.