Polymer nanocomposites, a class of innovative materials formed by polymer matrixes and nanoscaled fillers (e.g., carbon-based nanomaterials, inorganic/semiconductor nanoparticles, metal/metal-oxide nanoparticles, polymeric nanostructures, etc.), display enhanced mechanical, optoelectrical, magnetic, catalytic, and bio-related characteristics, thereby finding a wide range of applications in the biomedical field. In particular, the concept of supramolecular chemistry has been introduced into polymer nanocomposites, which creates myriad “smart” biomedical materials with unique physicochemical properties and dynamic tunable structures in response to diverse external stimuli. This review aims to provide an overview of the chemical composition, morphological structures, biological functionalities, and reinforced performances of supramolecular polymer nanocomposites. Additionally, recent advances in biomedical applications such as therapeutic delivery, bioimaging, and tissue engineering are also discussed, especially their excellent properties leveraged in the development of multifunctional intelligent biomedical materials.