Due to the potential of release and accumulation in the environment, nanoplastics have attracted an increasing attention. In this study, we investigated the effect of exposure to nanopolystyrene (30 nm) in nematode Caenorhabditis elegans after the fungal infection. After Candida albicans infection, exposure to nanopolystyrene (10 and 100 μg/L) for 24-h could cause the more severe toxicity on lifespan and locomotion behavior compared with fungal infection alone. The more severe activation of oxidative stress and suppression of SOD-3:GFP expression and mitochondrial unfolded protein response (mt UPR) were associated with this observed toxicity enhancement induced by nanopolystyrene exposure. Moreover, the more severe C. albicans colony formation and suppression of innate immune response as indicated by the alteration in expression of anti-microbial genes (abf-2, cnc-4, cnc-7, and fipr-22/23) further contributed to the formation of this toxicity enhancement induced by nanopolystyrene exposure. Our results demonstrated that short-term exposure to nanopolystyrene in the range of μg/L potentially enhances the adverse effects of fungal infection on organisms.