Metal-organic frameworks (MOFs) are emerging crystalline porous materials with significant potential in biomedical applications, particularly as drug delivery systems (DDS). MOFs, composed of metal ions or clusters linked by organic ligands, feature large surface areas, adjustable pores, and diverse functionalities. This review comprehensively examines MOFs as advanced DDS, detailing their structures, synthesis, and drug loading mechanisms. We highlight high drug loading capacity and controlled release capabilities of MOF. Developments of design strategies for MOF-based DDS, namely, surface functionalization for targeted delivery and stimuli-responsive MOFs for controlled release, have been discussed and explored. The use of MOFs for delivering therapeutic agents such as small molecules, peptides, proteins, nucleic acids, and cancer drugs is discussed. Challenges addressed include stability, degradation in biological environments, potential toxicity, and scalability. Advances in hybrid MOF-based DDS, integrating MOFs with polymers, lipids, or nanoparticles for improved delivery, are also examined.