Silk-based nanoparticles (SNPs) have gained noteworthy attention for making them an auspicious choice as a wonderful biomaterial in the medical field due to their versatility, adaptability, and biocompatibility. Functionalization and surface modification of silk-based nanoparticles improve their adaptability and efficiency in several bio-approaches. These alterations involve chemical, physical, or biological applications to modify the silk nanoparticle’s surface for improving stability, targeting, and specific delivery. Various strategies, including polymeric coatings, lipid encapsulation, and ligand conjugation, have been employed to optimize their physicochemical characteristics and biological interactions. These modifications make them highly effective for drug delivery, gene therapy, and tissue engineering by improving their hydrophilicity, cellular uptake, and controlled release profiles. The surface-engineered SNPs show enhanced bioavailability and reduced immunogenicity, ensuring safe and effective therapeutic applications. With advancements in nanotechnology, functionalized SNPs are emerging as promising carriers for precision medicine, particularly in cancer therapy, regenerative medicine, and antimicrobial treatments. This review provides a concise overview on the modern approaches of functionalization and surface modification of silk nanoparticles and their potential bio-applications.