As a broad class of porous nanomaterials, metal organic frameworks (MOFs) exhibit unique properties, such as broad tunability, high stability, atomically well-defined structure, and ordered uniform porosity. These features facilitate the rational design of MOFs as an outstanding nanomaterial candidate in biosensing, therapeutics delivery, and catalysis applications. Recently, novel modifications of the MOF nanoarchitecture and incorporation of synergistic guest materials have been investigated to achieve well-tailored functional design, gradually bridging the fundamental gap between structure and targeted activity. Specifically, the burgeoning studies of MOF-based high-performance biosensors have aimed to achieve high sensitivity, selectivity, and stability for a large variety of analytes in different sensing matrices. In this review, we elaborate the key roles of MOF nanomaterials in biosensors, including their high stability as a protective framework for biomolecules, their intrinsic sensitivity-enhancing functionalities, and their contribution of catalytic activity as a nanozyme. By examining the main structures of MOFs, we further identify varied structural engineering approaches, such as precursor tuning and guest molecule incorporation, that elucidate the concept of the structure-activity relationship of MOFs. Furthermore, we highlight the unique applications of MOF nanomaterials in electrochemical and optical biosensors for enhanced sensor performances. Finally, the challenges and future perspectives of developing next-generation MOF nanomaterials for biosensor applications are discussed.