The increasing number of biological applications for black phosphorus (BP) nanomaterials has precipitated considerable concern about their interactions with physiological systems. Here we demonstrate the adsorption of plasma protein onto BP nanomaterials and the subsequent immune perturbation effect on macrophages. Using liquid chromatography tandem mass spectrometry, 75.8% of the proteins bound to BP quantum dots were immune relevant proteins, while that percentage for BP nanosheet-corona complexes is 69.9%. In particular, the protein corona dramatically reshapes BP nanomaterial-corona complexes, influenced cellular uptake, activated the NF-κB pathway and even increased cytokine secretion by 2-4-fold. BP nanomaterials induce immunotoxicity and immune perturbation in macrophages in the presence of a plasma corona. These findings offer important insights into the development of safe and effective BP nanomaterial-based therapies.