Cyantraniliprole is a novel insecticide recently introduced for rice pest control that may cause potential threats to the red swamp crayfish (Procambarus clarkii) in rice−crayfish coculture systems. In this study, we investigated the acute toxicity of cyantraniliprole against P. clarkii with a LC 50 value of 149.77 mg/L (96 h), first. Some abnormal behaviors of P. clarkii treated with 125 mg/L cyantraniliprole, including incunabular hyperexcitability, imbalance, inactivity, and increased excretion were observed. Moreover, it was observed that exposure to 5 mg/L cyantraniliprole for 14 days resulted in histopathological alterations in abdominal muscle, gills, hepatopancreas, and intestines. Furthermore, exposure to 0.05 and 5 mg/L cyantraniliprole induced increased activities of several oxidative stress-related enzymes, which was verified by the upregulation of related genes. Additionally, dysregulation of the intestinal microbiota was determined via 16S rRNA sequencing. These results will provide the basis for the utilization of cyantraniliprole in the fields of rice−crayfish integrated system.