The remarkable progress of applied black phosphorus nanomaterials (BPNMs) is attributed to BP's outstanding properties. Due to its potential for applications, environmental release and subsequent human exposure are virtually inevitable. Therefore, how BPNMs impact biological systems and human health needs to be considered. In this comprehensive Minireview, the most recent advancements in understanding the mechanisms and regulation factors of BPNMs’ endogenous toxicity to mammalian systems are presented. These achievements lay the groundwork for an understanding of its biological effects, aimed towards establishing regulatory principles to minimize the adverse health impacts.