Metal-organic framework (MOF) nanocomposites have recently gained intensive attention for biosensing and disease therapy applications owing to their outstanding physiochemical properties. However, the direct growth of MOF nanocomposites is usually hindered by the mismatched lattice in the interface between the MOF and other nanocomponents. Surface ligands, molecules with surfactant-like properties, are demonstrated to exhibit the robust capability to modify the interfacial properties of nanomaterials and can be utilized as a powerful strategy for the synthesis of MOF nanocomposites. Besides this, surface ligands also exhibit significant functions in the morphological control and functionalization of MOF nanocomposites, thus greatly enhancing their performance in biomedical applications. In this review, the surface ligand-assisted synthesis and biomedical applications of MOF nanocomposites are comprehensively reviewed. Firstly, the synthesis of MOF nanocomposites is discussed according to the diverse roles of surface ligands. Then, MOF nanocomposites with different properties are listed with their applications in biosensing and disease therapy. Finally, current challenges and further directions of MOF nanocomposites are presented to motivate the development of MOF nanocomposites with elaborate structures, enriched functions, and excellent application prospects.