The particular physicochemical properties of nanomaterials are able to elicit unique biological responses. The property activity relationship is usually established for in-depth understanding of toxicity mechanisms and designing safer nanomaterials. In this study, the toxic role of specific crystallographic facets of a series of polyhedral lead sulfide (PbS) nanocrystals, including truncated octahedrons, cuboctahedrons, truncated cubes, and cubes, was investigated in human bronchial epithelial cells (BEAS-2B) and murine alveolar macrophages (RAW 264.7) cells. {100} facets were found capable of triggering facet-dependent cellular oxidative stress and heavy metal stress responses, such as glutathione depletion, lipid peroxidation, reactive oxygen species (ROS) production, heme oxygenase-1 (HO-1) and metallothionein (MT) expression, and mitochondrial dysfunction, while {111} facets remained inert under biological conditions. The {100}-facet-dependent toxicity was ascribed to {100}-facet-dependent lead dissolution, while the low lead dissolution of {111} facets was due to the strong protection afforded by poly(vinyl pyrrolidone) during synthesis. Based on this facet-toxicity relationship, a "safe-by-design" strategy was designed to prevent lead dissolution from {100} facets through the formation of atomically thin lead-chloride adlayers, resulting in safer polyhedral PbS nanocrystals.