Cadmium (Cd) is a common contaminant in environment. Crayfish are considered suitable for indicating the impact of heavy metals on the environment. However, there is limited information on the mechanisms causing damage to the hepatopancreas of Procambarus clarkii exposed to Cd. We exposed adult male P. clarkii to 2.0, 5.0, and 10.0 mg/L Cd for 24, 48, and 72 h to explore Cd toxicity. Afterwards, we measured bioaccumulations in the hepatopancreas and determined malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST). Additionally, the hepatopancreas histopathology was analyzed and the transcriptome analysis of the P. clarkii hepatopancreas under Cd stress was conducted. The results revealed that hepatopancreas could accumulate Cd in a time- and dose-dependent manner. Cd induced significant changes in MDA content and antioxidant enzyme activity. Severe histological alterations were observed in crayfish hepatopancreas. After 72 h exposure to 2.0, 5.0, and 10.0 mg/L Cd, transcriptome analysis identified 1061, 747, and 1086 differentially expressed genes (DEGs), respectively. Exposure to 5.0 mg/L Cd inhibited heme binding, tetrapyrrole binding, iron ion binding and activity of oxidoreductase and sulfotransferase, while exposure to 10.0 mg/L Cd enhanced the export of matters from nucleus. In the hepatopancreas treated with 10.0 mg/L Cd, pathways related to diseases and immune system were significantly enriched. Meanwhile, 31, 31, 24, 7, and 12 identified DEGs were associated with the oxidation-reduction process, immune system, ion homeostasis, digestion and absorption, and ATPases, respectively. Our study provides comprehensive information for exploring the toxic mechanisms of Cd and candidate biomarkers for aquatic Cd risk evaluation.