Microplastics (MPs) are newly emerged pollutants found in water and soil, while microcystin-leucine arginine (MC-LR) is often detected in drinking water and water products, both posing serious threats to aquatic environment and food safety. MPs can serve as carriers of MC-LR. These pollutants are often found together, rather than separately. This study focused on assessing the neurotoxicity of co-exposure to MC-LR and PS in Caenorhabditis elegans (C. elegans) after combined exposure to these two pollutants. Exposure to varying concentrations of polystyrene (PS) and MC-LR individually caused a dose-dependent decrease in the locomotion behaviors of C. elegans. Exposure to either of these substances alone caused damage to the phenotypic indicators of the C. elegans. To further explore the additional damage caused by the combined exposure of PS and MC-LR, the low, medium, and high combined dose groups were selected based on the locomotion behaviors and survival results. Combined exposure increased the level of oxidative stress indicators and resulted in neuronal loss. It also reduced serotonin, glutamate, GABA, and dopamine neurotransmitters levels, without affecting cholinergic neurons. The expression of neurotransmitter-related genes also decreased. The high-dose group showed the most significant effects. This article is the first to study the combined effect of PS and MC-LR on C. elegans nervous systems, offering novel insights into the risks posed by co-occurring contaminants and their implications for aquatic ecosystems and food safety.