As a novel member of the two-dimensional nanomaterial family, mono- or few-layer black phosphorus (BP) with direct bandgap and high charge carrier mobility is promising in many applications such as microelectronic devices, photoelectronic devices, energy technologies, and catalysis agents. Due to its benign elemental composition (phosphorus), large surface area, electronic/photonic performances, and chemical/biological activities, BP has also demonstrated a great potential in biomedical applications including biosensing, photothermal/photodynamic therapies, controlled drug releases, and antibacterial uses. The nature of the BP–bio interface is comprised of dynamic contacts between nanomaterials (NMs) and biological systems, where BP and the biological system interact. The physicochemical interactions at the nano–bio interface play a critical role in the biological effects of NMs. In this review, we discuss the interface in the context of BP as a nanomaterial and its unique physicochemical properties that may affect its biological effects. Herein, we comprehensively reviewed the recent studies on the interactions between BP and biomolecules, cells, and animals and summarized various cellular responses, inflammatory/immunological effects, as well as other biological outcomes of BP depending on its own physical properties, exposure routes, and biodistribution. In addition, we also discussed the environmental behaviors and potential risks on environmental organisms of BP. Based on accumulating knowledge on the BP–bio interfaces, this review also summarizes various safer-by-design strategies to change the physicochemical properties including chemical stability and nano–bio interactions, which are critical in tuning the biological behaviors of BP. The better understanding of the biological activity of BP at BP–bio interfaces and corresponding methods to overcome the challenges would promote its future exploration in terms of bringing this new nanomaterial to practical applications.