Nickel pollution adversely affects human health and causes various disorders, mainly hepatic and renal dysfunction. The present work focused on a comparative evaluation of the pure form of curcumin (CU) with curcumin-encapsulated chitosan nanoconjugates (CS/CU NCs), on mitigation of the delirious effects of Ni on hepatorenal tissue. Forty-two male rats were allocated into 6 groups (n = 7 for each) as follows: (1) control, (2) CU, (3) CS/CU NCs, (4) Ni, (5) Ni + CU, (6) Ni + CS/CU NCs. After 30 days, blood and tissue (liver and kidneys) were collected to measure hepatorenal biomarkers, oxidant/antioxidant balance, inflammatory gene expression, liver and kidney histopathology, and immunohistochemistry. Results revealed disruption of hepatorenal functions, oxidative stress, and inflammatory markers at biochemical and molecular levels associated with severe hepatorenal histopathological alterations and abnormal immunohistochemical tissue expression for caspase-3 and cyclooxygenase-2. On the contrary, the treatment of Ni-intoxicated rats with CS/CU NCs markedly mitigated the adverse effect of Ni on hepatorenal tissue via regulation of oxidative stress, inflammatory, and apoptotic markers. The present study provides a novel nanoformulation for curcumin using CS NPs encapsulation that selectively targets the injured cells and improves the beneficial effect of CU via enhancing the antioxidant activity and regulating both inflammatory and apoptotic markers.