Several obstacles such as drug insolubility, non-specificity, poor bioavailability, high dose requirements, cytotoxicity, blood-brain barrier, drug resistance and biofilm development generally hamper medical conventional chemotherapeutic treatments leading to aggravation of disease-state causing ultimate death of patient. To overcome the biological barriers, nanotechnology-based selenium nanoparticles (SeNPs) have attracted attention recently as drug delivery system as well as nanomedicine in combating several diseases such as inflammation, arthritis, diabetes, infection, neurological disorders, and cancer. The biocompatible, degradable, less toxic, quantum sized with large surface-to-volume ratio, largely differed surface atoms and spherical shaped SeNPs may be surface-functionalized with ligands and / or encapsulated with polymeric vesicle and cargo for biomedical applications to target their payloads to specific cells with controlled release. Moreover, SeNPs have antioxidant, anti-inflammatory, anti-microbial, anti-carcinogenic and immune regulatory activities as a delivery system. Therefore, cargo loaded SeNPs attached with ligands and / or vesicles may be utilized for synergistic bio medicinal applications to get their higher bioavailability and therapeutic efficacies with sustained drug release to specific site/s of interest against diseases. This review elucidates the current advances regarding their synthesis, functionalization, mechanism of action, biomedical applications, toxicity, and elimination as a potent targeted delivery system against different diseases.