Ion channels on cytoplasmic membrane function to sense various environmental stimuli. We here determined the changes of genes encoding ion channels in Caenorhabditis elegans after exposure to polystyrene nanoparticles (PS-NPs). Exposure to 1-1000 μg/L PS-NPs could increase expressions of egl-19, mec-10, trp-4, trp-2, tax-4, cca-1, unc-2, and unc-93, and decrease the expressions of cng-3, mec-6, ocr-2, deg-1, exc-4, kvs-1, and eat-2. Among these 15 ion channel genes, RNAi knockdown of cng-3 or eat-2 caused resistance to PS-NPs toxicity and RNAi knockdown of egl-19, cca-1, tax-4, or unc-93 induced susceptibility to PS-NPs toxicity, suggesting that cng-3, eat-2, egl-19, cca-1, tax-4, and unc-93 were involved in the control of PS-NPs toxicity. EGL-19 and CCA-1 functioned in intestinal cells to control PS-NPs toxicity, and CNG-3, EAT-2, EGL-19, TAX-4, and UNC-93 functioned in neuronal cells to control PS-NPs. Moreover, in intestinal cells of PS-NPs exposed worms, cca-1 RNAi knockdown decreased elt-2 expression, and egl-19 RNAi knockdown decreased daf-16 and elt-2 expressions. In neuronal cells of PS-NPs exposed worms, eat-2 RNAi knockdown increased jnk-1, mpk-1, and dbl-1 expressions, unc-93 RNAi knockdown decreased mpk-1 and daf-7 expressions, and tax-4 RNAi knockdown decreased jnk-1 and daf-7 expressions. Therefore, two molecular networks mediated by ion channels in intestinal cells and neuronal cells were dysregulated by PS-NPs exposure in C. elegans. Our data suggested that the dysregulation in expressions of these ion channels mediated a protective response to PS-NPs in the range of μg/L in worms.