2D boron nitride (BN) and molybdenum disulfide (MoS₂ ) materials are increasingly being used for applications due to novel chemical, electronic, and optical properties. Although generally considered biocompatible, recent data have shown that BN and MoS₂ could potentially be hazardous under some biological conditions, for example, during, biodistribution of drug carriers or imaging agents to the liver. However, the effects of these 2D materials on liver cells such as Kupffer cells (KCs), liver sinusoidal endothelial cells, and hepatocytes, are unknown. Here, the toxicity of BN and MoS₂ , dispersed in Pluronic F87 (designated BN-PF and MoS₂ -PF) is compared with aggregated forms of these materials (BN-Agg and MoS₂ -Agg) in liver cells. MoS₂ induces dose-dependent cytotoxicity in KCs, but not other cell types, while the BN derivatives are non-toxic. The effect of MoS₂ could be ascribed to nanosheet dissolution and the release of hexavalent Mo, capable of inducing mitochondrial reactive oxygen species generation and caspases 3/7-mediated apoptosis in KUP5 cells. In addition, the phagocytosis of MoS₂ -Agg triggers an independent response pathway involving lysosomal damage, NLRP3 inflammasome activation, caspase-1 activation, IL-1β, and IL-18 production. These findings demonstrate the importance of Mo release and the state of dispersion of MoS₂ in impacting KC viability.