The emergence of nanotechnology has provided the possibilities to overcome the potential problems associated with the development of pharmaceuticals including the low solubility, non-specific cellular uptake or action, and rapid clearance. Regarding the biomaterials (BMs), huge efforts have been made for improving their multi-functionalities via incorporation of various nanomaterials (NMs). Nanocomposite hydrogels with suitable properties could exhibit a variety of beneficial effects in biomedicine particularly in the delivery of therapeutics or tissue engineering. NMs including the silica- or carbon-based ones are capable of integration into various BMs that might be due to their special compositions or properties such as the hydrophilicity, hydrophobicity, magnetic or electrical characteristics, and responsiveness to various stimuli. This might provide multi-functional nanobiomaterials against a wide variety of disorders. Meanwhile, inappropriate distribution or penetration into the cells or tissues, bio-nano interface complexity, targeting ability loss, or any other unpredicted phenomena are the serious challenging issues. Computational simulations and models enable development of NMs with optimal characteristics and provide a deeper knowledge of NM interaction with biosystems. This review highlights the biomedical significance of the multifunctional NMs particularly those applied for the development of 2-D or 3-D BMs for a variety of applications including the site-specific delivery of therapeutics. The powerful impacts of the computational techniques on the design process of NMs, quantitation and prediction of protein corona formation, risk assessment, and individualized therapy for improved therapeutic outcomes have also been discussed.