Engineered nanomaterials (ENMs) with different topographies provide effective nano-bio interfaces for controlling the differentiation of stem cells. The interaction of stem cells with nanoscale topographies and chemical cues in their microenvironment at the nano-bio interface can guide their fate. The use of nanotopographical cues, in particular nanorods, nanopillars, nanogrooves, nanofibers, and nanopits, as well as biochemical forces mediated factors, including growth factors, cytokines, and extracellular matrix proteins, can significantly impact stem cell differentiation. These factors were seen as very effective in determining the proliferation and spreading of stem cells. The specific outgrowth of stem cells can be decided with size variation of topographic nanomaterial along with variation in matrix stiffness and surface structure like a special arrangement. The precision chemistry enabled controlled design, synthesis, and chemical composition of ENMs can regulate stem cell behaviors. The parameters of size such as aspect ratio, diameter, and pore size of nanotopographic structures are the main factors for specific termination of stem cells. Protein corona nanoparticles (NPs) have shown a powerful facet in stem cell therapy, where combining specific proteins could facilitate a certain stem cell differentiation and cellular proliferation. Nano-bio reactions implicate the interaction between biological entities and nanoparticles, which can be used to tailor the stem cells' culmination. The ion release can also be a parameter to enhance cellular proliferation and to commit the early differentiation of stem cells. Further research is needed to fully understand the mechanisms underlying the interactions between engineered nano-bio interfaces and stem cells and to develop optimized regenerative medicine and tissue engineering designs.