Inorganic arsenical compounds, such as arsenic trioxide (ATO), are toxic environmental contaminants that occur widely in soil, water, and biological systems. Besides, zinc oxide nanoparticles (ZNPs) have been recently incorporated in various industrial and medicinal applications. Thus, their co-existence in the environment could widely occur. This study examined the potential protective activity of gallic acid (GA, 20 mg/kg b. wt) against the harmful impacts of 60-day co-exposure to ATO (8 mg ATO/kg b. wt) and ZNPs (100 mg ZNPs/kg b. wt) on the kidneys of rats. The results indicated that ZNPs and/or ATO exposure resulted in increased serum levels of markers associated with renal damage, an imbalance in electrolytes (sodium, potassium, and calcium), diminished levels of antioxidant enzymes in the kidneys, and an increased malondialdehyde (MDA) concentration. Furthermore, ZNPs and/or ATO co-exposed rats demonstrated markedly increased levels of renal zinc (Zn) and arsenic (As), accompanied by pronounced histopathological alterations, including interstitial nephritis, renal tubular necrosis, and vascular wall thickening. Immunohistochemical analysis revealed that exposure to ZNPs and/or ATO reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) while increasing that of heat shock protein 90 (HSP90) in kidney tissues. Co-exposure to ZNPs and ATO produced more pronounced alterations, including increased serum uric acid and creatinine, decreased sodium levels, reduced renal GPx activity, increased MDA content, greater renal accumulation of As and Zn, and diminished Nrf2 expression, compared with individual exposures, suggesting additive toxic effects. However, GA notably reduced renal tissue damage, oxidative stress, and disturbances in renal function and electrolyte balance in rats co-exposed to ZNPs and ATO. Conclusively, the study found that exposure to ZNPs and ATO, especially when combined, was toxic to the kidneys, leading to impaired renal function through increased oxidative stress and disrupted electrolyte balance. However, GA effectively protected kidney health at the administered doses by counteracting these effects through its antioxidant properties and by modulating cellular defense mechanisms involving Nrf2 and HSP90.