Objective To explore the protective effect and mechanism of curcumin (CUR) on acetaminophen (APAP) -induced acute kidney injury in rats. Methods Forty-eight male SD rats were randomly divided into normal, model, positive, CUR low (50 mg/ kg), medium (100 mg/ kg), and high (200 mg/ kg) dose group. After intragastric administration of N-acetylcysteine ( NAC) and CUR for 10 days, acute kidney injury models were established by intragastric administration of 2 g/ kg APAP. After 24 hours, blood was collected and kidneys were collected, the kidney index was calculated, the levels of serum creatinine (Cr) and blood urea nitrogen (BUN) were measured. Pathological injury of the kidney was evaluated by HE staining, activities of glutathione (GSH), total superoxide dismutase (T-SOD), and catalase (CAT), and the malondialdehyde (MDA) level in kidneys were assessed. Expression of Trx-1, TXNIP, and NLRP3 inflammasome in kidneys was detected by Western blot. Results Compared with the normal group, the kidney index and the levels of serum Cr and BUN in the model group were increased significantly (P< 0. 01), pathological sections showed obvious lesions in the kidney, activities of GSH, T-SOD, and CAT in kidneys were significantly decreased (P< 0. 01), the MDA content was significantly increased (P< 0. 01), Trx-1 expression in the kidney was significantly decreased (P< 0. 05), and expression of TXNIP, NLRP3, ASC, Cleaved caspase-1, and mature IL-1β was significantly upregulated (P< 0. 01). Compared with the model group, the kidney index in CUR medium, and high dose groups was significantly decreased (P< 0. 01), pathological damage had improved, levels of serum Cr and BUN were decreased (P< 0. 01), activities of GSH, T-SOD, and CAT in the kidney were increased, MDA content was decreased (P< 0. 05 or P< 0. 01), Trx-1 expression was significantly increased (P< 0. 05 or P< 0. 01), and expression of TXNIP, NLRP3, ASC, Cleaved caspase-1, and mature IL-1β protein was significantly downregulated ( P< 0. 01). Conclusions CUR pretreatment alleviates acetaminophen-induced acute kidney injury by regulating the Trx-1/ TXNIP/ NLRP3 signaling pathway in rats.