In this study, the impact of nimesulide on oxidative stress induced by cisplatin in rat duodenum and jejunum tissue was assessed by evaluating the biochemical and histopathological changes. The rats in the study were assigned to three groups: the control group and cisplatin (Cis) group were given distilled water, and the nimesulide + cisplatin (Nim + Cis) group was given nimesulide (50 mg/kg) orally for seven days. The Cis and Nim + Cis groups were injected with a single dose of intraperitoneal cisplatin (6 mg/kg) on the first day. After the rats were euthanized, the duodenum and jejunum of each rat was removed for the assessment of biochemical markers and histopathological evaluation. Cisplatin administration in the Cis group resulted in increased levels of malondialdehyde and nitric oxide and decreased levels of total glutathione, glutathione reductase, and catalase compared to the healthy and Nim + Cis groups. Nimesulide significantly inhibited the increase of oxidants (p < 0.001) and the decrease of antioxidants caused by cisplatin (p < 0.001). Inflammation, damage to the villus epithelium, hemorrhage, and capillary proliferation were determined histopathologically in the Cis group. The results of this study indicate that oxidative stress caused by cisplatin may be preventable by co-administered nimesulide.