The applicability of nanomaterials has evolved in biomedical domains thanks to advances in biocompatibility strategies and the mitigation of cytotoxic effects, allowing diagnostics, imaging, and therapeutic approaches. The application of nanoparticles (NP), particularly metal nanoparticles (mNPs), such as gold (Au) and silver (Ag), includes inherent challenges related to the material characteristics, surface modification, and bioconjugation techniques. By tailoring the surface properties through appropriate coating with biocompatible molecules or functionalization with active biomolecules, researchers can reach a harmonious interaction with biological systems or samples (mostly fluids or tissues). Thus, this review highlights the mechanisms associated with the obtention of biocompatible mNP and presents a comprehensive overview of methods that facilitate safe and efficient production. Therefore, we consider this review to be a valuable resource for all researchers navigating this dynamic field.