<p>Oxidative stress and inflammation are central mediators in the initiation and progression of hepatic dysfunction and its associated metabolic complications. Although allopathic, homeopathic, and herbal drugs are commonly used to treat liver- and pancreas-related disorders, their clinical utility is often limited by poor solubility, low stability, rapid elimination, and suboptimal bioavailability. Silymarin, a well-established hepatoprotective phytodrug, exhibits broad biological activity; however, its therapeutic efficacy is constrained by these pharmacokinetic limitations. To overcome these challenges, silymarin-based cerium oxide nanoparticles (S-CeONPs), previously synthesized and characterized in our earlier work, were employed for in vivo evaluation due to their strong in vitro biological potential. Given the central regulatory role of the liver in metabolic homeostasis, the disease models investigated in this study were selected as interconnected manifestations of oxidative stress–driven hepatic dysfunction rather than independent pathological entities. In vivo findings demonstrated that S-CeONPs significantly restored hepatic biochemical markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and serum bilirubin, in mice with paracetamol-induced hepatotoxicity. Furthermore, S-CeONPs markedly improved lipid profiles by reducing total cholesterol, triglycerides, and low-density lipoprotein (LDL) levels while increasing high-density lipoprotein (HDL) levels in high-fat diet-induced hyperlipidaemic mice, confirming their hepatoprotective and anti-atherogenic potential. In addition, oral administration of S-CeONPs significantly reduced blood glucose levels, inflammatory responses, and serum creatinine in mice with alloxan-induced diabetes and carrageenan-induced inflammation compared with control and silymarin-treated groups. The enhanced therapeutic efficacy of the nanoformulation over native silymarin is attributed to its favorable physicochemical properties, which improve bioavailability and potentiate antioxidant defense by restoring key enzymatic markers, including glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA). Collectively, these findings indicate that hepatic-targeted redox modulation by S-CeONPs leads to coordinated improvements in systemic metabolic and inflammatory disturbances, highlighting their potential as a multifunctional therapeutic platform for oxidative stress–associated chronic diseases.</p>