This study aimed to investigate the protective effects of curcumin and selenium nanoparticles, both individually and in combination, against aluminum chloride (AlCl3)-induced hepatorenal toxicity in rats. Hepatorenal toxicity was induced through oral administration of AlCl3 (200 mg/kg body weight/day) for 30 days. Thirty male Sprague–Dawley rats were randomly assigned into five groups: the control group received the vehicle, the second group received AlCl3 only, while the third, fourth, and fifth groups were treated with nanocurcumin (50 mg/kg body weight/day), nano-selenium (0.4 mg/ kg body weight/day), and their combination, respectively, alongside AlCl3 for the same duration. Post-treatment evaluations included biochemical, molecular, histopathological, and immunohistochmical analyses. AlCl3 intoxication resulted insignificant biochemical disruptions, elevating oxidative stress markers such as malondialdehyde (MDA) and nitric oxide (NO), while diminishing the activities of catalase (CAT) and superoxide dismutase (SOD). Furthermore, expression levels of nuclear factor-erythroid 2-related factor 2 (Nrf2) mRNA, along with tumour necrosis factor-alpha (TNF-α) and caspase-3, were significantly elevated, indicating substantial hepatic and renal damage. In contrast, treatment with nanocurcumin, nano-selenium, and their combination notably improved biochemical markers, reducing MDA and NO levels, and enhancing SOD and CAT activities. Additionally, these treatments inhibited apoptosis by reducing caspase-3 and TNF-α expression, as well as Nrf2 levels. Histopathological findings further validated the protective effects of nanocurcumin, nano-selenium, and their combination against AlCl3 toxicity. Overall, the results suggest that curcumin and selenium nanoparticles protect hepatic and renal tissues from AlCl3-induced damage by enhancing antioxidant defense mechanisms and suppressing inflammation and apoptosis.