Emerging transition-metal dichalcogenide (TMDC) nanosheets, such as WS2 nanosheets, have shown tremendous potential for use in many fields such as intelligent manufacturing and environmental protection. However, considerable knowledge gaps still exist regarding the impact of TMDCs on environmental risks, especially risks involving organic pollutants. Here, a synergistic toxicity between WS2 nanosheets and organic pollutants (triclosan or tris(1,3-dichloro-2-propyl) phosphate) was found using the median-effect and combination index equations. In particular, the effect of synergy had a higher magnitude at low cytotoxicity levels and a noncytotoxic concentration of WS2 nanosheets clearly enhanced the cytotoxicity and intracellular accumulation of organic pollutants. On the one hand, WS2 nanosheets damaged the plasma membrane and cytoskeleton, resulting in increased membrane permeability and organic pollutant uptake. On the other hand, as shown by fluorescence substrate accumulation experiments and molecular dynamics simulations, WS2 nanosheets affected the secondary structure of the efflux pumps and competitively bound with efflux pumps, blocking xenobiotic removal. This work emphasized that TMDCs, especially at the noncytotoxic level, in combination with organic pollutants caused damage that cannot be ignored, providing insight into comprehensive safety assessment and the specific toxicological mechanisms of TMDCs that accompany organic pollutant exposure.