<p>Di-n-butyl phthalate (DBP) is a conventional plasticizer known to induce hepatotoxicity and nephrotoxicity through oxidative stress and apoptosis. In contrast, curcumin, a polyphenolic compound from <i>Curcuma longa</i>, has significant antioxidant and anti-apoptotic activity; however, its therapeutic efficiency is limited due to poor absorption and low bioavailability. Nanoliposomes can significantly enhance the stability and absorption of curcumin, thereby improving its protective efficacy. Therefore, this study aimed to evaluate the protective effects of curcumin-loaded nanoliposomes against DBP-induced hepatotoxicity and nephrotoxicity in rats. The adult male rats were randomly assigned to four groups: control, CUR-NLs (200 mg/kg/day), DBP (500 mg/kg/day), and DBP + CUR-NLs, for 60 days. DBP administration significantly raised blood levels of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, uric acid, urea, and malondialdehyde (MDA), while lowering serum protein fractions and catalase (CAT) activity. Gene expression analysis revealed that nuclear factor erythroid 2-related factor 2 (<i>Nrf2</i>), Catalase (CAT), superoxide dismutase (SOD), and B-cell lymphoma-2 (BCL2) were downregulated, whereas cytochrome c (CYCS) and Bcl-2-associated X (Bax) were upregulated, and caspase-3 immunoreactivity increased. Compared with DBP-treated rats, co-treatment with CUR-NLs significantly restored protein metabolism, decreased lipid peroxidation, increased antioxidant defenses, raised anti-apoptotic markers, and improved histopathological and immunohistochemical findings. These results indicate that CUR-NLs effectively mitigate DBP-induced hepatorenal injury by restoring redox homeostasis and regulating apoptotic signaling pathways, suggesting that CUR-NLs represent a promising nanotechnological strategy for preventing DBP-induced organ toxicity.</p>