Nanoplastics are widely distributed in the environment and can adsorb heavy metals, which poses a potential threat to human health through food chain. It is necessary to assess the combined toxicity of nanoplastics and heavy metals. The adverse effect of Pb and nanoplastics on liver, single or in combination, was evaluated in this study. The results showed that the Pb content in co-exposure group of nanoplastics and Pb (PN group) was higher than the group exposed to Pb alone (Pb group). And more severe inflammatory infiltration was observed in liver sections of PN group. The level of inflammatory cytokines and malondialdehyde were increased, while the superoxide dismutase activity was decreased in liver tissues of PN group. Moreover, the gene expression level of , and , which is related to antioxidation, was downregulated. And the expression level of cleaved-Caspase9 and cleaved-Caspase3 were increased. However, with the supplementation of oxidative stress inhibitor N-Acetyl-L-cysteine, liver damage shown in PN group was evidently alleviated. In summary, nanoplastics evidently exacerbated the deposition of Pb in liver and potentially aggravated the Pb-induced liver toxicity by activating oxidative stress.