Arsenic is widely available in the environment and arsenic toxicity is a public health problem of serious concern worldwide. Zingerone is a promising phytochemical with various pharmacological effects. In this study, the potential protective effect of zingerone against sodium arsenite (NaAsO, SA) induced nephrotoxicity was investigated. Thirty-five male Sprague-Dawley rats were divided into five different groups as control, zingerone, SA, SA + zingerone 25, SA + zingerone 50. SA was administered alone at a dose of 10 mg/kg for 14 days or given 30 min before zingerone (25 mg/kg or 50 mg/kg) treatment. At the end of the experiment, the kidney tissues was examined biochemically, molecularly and microscopically. SA toxicity was associated with increased malondialdehyde level, whereas glutathione, superoxide dismutase, catalase, and glutathione peroxidase were decreased. Administration of SA caused inflammation in the kidney tissue by upregulation of NF-κB and IL-1β, TNF-α, IL-6, iNOS, COX-2, MAPK14, MAPK15, JNK. SA administration caused apoptosis in the kidney by upregulating caspase-3 and Bax levels and downregulating Bcl-2, and autophagy by activating beclin-1. Also, SA administration showed a suppressive effect on AKT2 and FOXO1 mRNA transcript levels. All these factors impair kidney function and increase creatinine and urea levels, resulting in pathological changes and a decrease in nephrin. Treatment with zingerone at doses of 25 and 50 mg/kg significantly reduced oxidative stress, inflammation, apoptosis and autophagy in kidney tissue. In addition, it was confirmed by histological evaluation as well as serum urea and creatinine levels that kidney damage due to SA toxicity can be modulated by zingerone administration.