This study aimed to evaluate the synergistic effects of both vanillin (V) and chitosan nanoparticles (CNPs) in alleviating hepatotoxicity, oxidative injury, and genotoxicity induced by d-galactose (DG) and resulted from aging in male albino rats. Male Wistar rats were divided into seven groups (10 rats/group) as follows: control group, (DG) group (100 mg/kg), (V) group (100 mg/kg), CNPs either (low dose (LD) or CNPs (high dose (HD) (140 mg/kg) and (280 mg/kg), and CNPs (LD and HD) dose with V- and DG plus V-treated groups. The CNPs were characterized by transmission electron microscopy (TEM), zeta potential, and size distribution of nanoparticles. After 60 consecutive days of exposure, some biochemical parameters were measured as hepatic aminotransferases enzymes, lipid profile, tumor necrosis factor alpha, interleukin-6 (IL-6), markers of inflammation, tissue damage lactate dehydrogenase, C-reactive protein (CRP), mitochondrial potential activities, myeloperoxidase, xanthine oxidase, CRP, succinate dehydrogenase, mitochondria membrane potential, malondialdehyde levels and antioxidant enzymes (superoxide dismutase, catalase, glutathione reductase, and glutathione S-transferase), and adenosine triphosphate content with histological, alkaline comet assay, and TEM examination of the hepatic tissues. CNPs showed that size distribution (polydispersity index) 0.350 nm and the zeta potential measurement of CNPs were found to be -14.9 mV which revealed the high stability of CNPs. DG induced biochemical and cellular alterations in the hepatic tissues. CNPs and V synergistically afforded protection against hepatic injury and oxidative stress resulting from aging that was induced by DG. Consequently, CNPs were an effective agent in the drug delivery in the hepatic diseases medications and act as a carrier for V and thus make synergistic effect between CNPs and V that achieved the high antioxidant capacities. CNPs and V improved the hepatic enzymes, which act as anti-inflammatory and antigenotoxicity, and improved the antioxidant capacities in the hepatic tissues.