<p>Metal–organic frameworks (MOFs), made up of metal ions and organic ligands, possess high surface area, tunable pores, and chemical function, which gives them the capability to control their interaction with biomolecules and living systems. These unique properties give rise to the expansion of MOFs developed from their traditional applications like gas adsorption and catalysis to their modern applications in drug delivery systems, cancer therapy, biomedical imaging, antimicrobial therapy, and tissue engineering. The biologically important metal nodes such as Zn²⁺, Fe²⁺/³⁺, Cu²⁺, Mg²⁺, and Mn²⁺ confer catalytic properties, antimicrobial activity, and biocompatibility enabling MOFs to function as active participants rather than passive carriers in biological systems. Nanoscale MOFs have enhanced surface accessibility and rapid interaction with biological entities, while bulk MOFs have provided structural support for repeated use in biocatalysis and separation. MOF-based platforms have offered high drug-loading capacity and specific therapeutic efficacy in cancer treatment through multimodal approaches, such as photodynamic, photothermal, and chemodynamic therapy. In cancer therapy, MOF-mediated chemodynamic therapy achieves ~ 29.9% doxorubicin loading with sustained Fenton-catalytic ROS generation; porphyrinic Zr-MOF platforms deliver PDT–chemotherapy synergy with high tumor cell cytotoxicity; and sonodynamic/radiodynamic MOF platforms suppress metastasis at low X-ray doses. MOFs have demonstrated strong antimicrobial properties and have vast potential in tissue engineering through ion delivery and scaffold approaches. In antimicrobial applications, ZIF-8 nanodagger arrays achieve greater than 7-log bacterial reduction against <i>Escherichia coli</i> and <i>Staphylococcus aureus</i> via physical membrane penetration. ATP-responsive ZIF-90/NIR nanoprobes achieve 32-fold fluorescence turn-on at 705&#xa0;nm for real-time tumor imaging. However, there are still issues associated with MOF toxicity, biodegradability, scalability, and biomedical translation. Overcoming these challenges through MOF design and standardized assessment will be essential for the development of safe and clinical viable biomedical applications of MOFs.</p> Graphical abstract <p></p>