Pesticides are important for agricultural development; however, animals involved in rice-fish farming absorb the pesticides used during the farming process. Thiamethoxam (TMX) is extensively used in agriculture and is gradually occupying the market for traditional pesticides. Therefore, this study aimed to investigate whether selenomethionine (SeMet) could affect the survival rate, bioaccumulation of TMX, serum biochemical parameters, lipid peroxidation, antioxidants in the hepatopancreas, and expression of stress genes after exposure of red swamp crayfish to 10 ppt TMX for 7 days. The results showed that the survival rate significantly increased and the bioaccumulation of TMX significantly decreased with SeMet administration (P < 0.05). Furthermore, severe histological damage to the hepatopancreas of red crayfish was observed after exposure to TMX; however, this damage was alleviated after SeMet administration. SeMet also significantly reduced the TMX-induced changes in serum biochemical parameters, malondialdehyde content, and antioxidant enzyme activity in crayfish hepatopancreas (P < 0.05). Notably, analysis of the expression of 10 stress response genes showed that 0.5 mg/kg SeMet might decrease cell damage in the hepatopancreas. Consequently, our findings suggest that higher levels of TMX in crayfish may cause hepatopancreatic cell toxicity, which can be harmful to human health; however, SeMet could mitigate these effects, providing an understanding of pesticide compounds and food safety.