Antimicrobial resistance has rendered many conventional therapeutic measures, such as antibiotics, ineffective. This makes the treatment of infections from pathogenic micro-organisms a major growing health, social, and economic challenge. Recently, nanomaterials, including two-dimensional (2D) materials, have attracted scientific interest as potential antimicrobial agents. Many of these studies, however, rely on the input of activation energy and lack real-world utility. In this work, we present the broad-spectrum antimicrobial activity of few-layered black phosphorus (BP) at nanogram concentrations. This property arises from the unique ability of layered BP to produce reactive oxygen species, which we harness to create this unique functionality. BP is shown to be highly antimicrobial toward susceptible and resistant bacteria and fungal species. To establish cytotoxicity with mammalian cells, we showed that both L929 mouse and BJ-5TA human fibroblasts were metabolically unaffected by the presence of BP. Finally, we demonstrate the practical utility of this approach, whereby medically relevant surfaces are imparted with antimicrobial properties via functionalization with few-layer BP. Given the self-degrading properties of BP, this study demonstrates a viable and practical pathway for the deployment of novel low-dimensional materials as antimicrobial agents without compromising the composition or nature of the coated substrate.