Plastics in the environment can break down into nanoplastics (NPs), which pose a potential threat to public health. Studies have shown that the nervous system constitutes a significant target for nanoplastics. However, the potential mechanism behind nanoplastics' neurotoxicity remains unknown. This study aimed to investigate the role of lncRNA in the depressive-like responses induced by exposure to 25 nm polystyrene nanoplastics (PS NPs). Forty mice were divided into four groups administered doses of 0, 10, 25, and 50 mg/kg via gavage for 6 months. After conducting behavioral tests, RNA sequencing was used to detect changes in mRNAs, miRNAs, and lncRNAs in the prefrontal cortex of the mice in the 0 and 50 mg/kg PS NPs groups. The results revealed that mice exposed to chronic PS NPs developed depressive-like responses in a dose-dependent manner. It was demonstrated that 987 mRNAs, 29 miRNAs, and 116 lncRNAs were significantly different between the two groups. Then, a competing endogenous RNA (ceRNA) network containing 6 lncRNAs, 18 miRNAs, and 750 mRNAs was constructed. Enrichment results suggested that PS NPs may contribute to the onset of depression-like responses through the activation of axon guidance, neurotrophin-signaling pathways, and dopaminergic synapses. This study provided evidence of the molecular relationship between PS NPs and depression-like responses.