Abstract: Background and Objective: Ageing is frequently accompanied by the occurrence of several diseases, such as Alzheimer’s and disturbance of vital organs like liver, the combination between some compounds with antioxidant properties are considered a new hope for treatment of aging consequences, so this paper aimed to evaluate the synergistic effect between chitosan nanoparticles and lycopene in ameliorating liver functions and alleviate hepatotoxicity and oxygen free radicals which are a reactive species that are permanently liberated in living cells and increased greatly in aging and causes health disturbances. This study aimed to synthesis chitosan nanoparticles (CHNPs), to determine their characteristics and to estimate the synergistic role of CHNPs incorporation with lycopene (Ly) against oxidative stress of aging and hepatotoxicity. Materials and Methods: Male wistar rats were divided into 9 groups (10 rats/group) as follow: Control group, D-galactose group(100 mg kg–1), CHNPs either (low dose) or (high dose) (140 or 280 mg kg–1), Ly group (20 mg kg–1), CHNPs either low dose or high dose with Ly and D-gal plus Ly and/or CHNPs with Low and high dose treated groups. The CHNPs were characterized by TEM, Zeta potential and size distribution of particles. At the end of the experiment, some biochemical parameters were measured as lipid profile, tumor marker TNF-α and IL-6, markers of inflammation and tissue damage LDH and CRP with histological, comet assay and TEM examination of liver tissues. Results: Chitosan showed size distribution (pdi) 0.370 nm. D-galactose induced hepatic biochemical alterations and cellular changes. CHNPs in two doses either low or high dose alone or combined with Ly significantly elicited remarkable amelioration in liver enzymes biomarkers, improved lipid profile, decreased tumor necrosis factor-α and IL-6, enhanced antioxidant enzymes as SOD, CAT and GPx with decreasing marker of lipid peroxidation and proved by structural alterations in TEM, histological and comet assay of liver tissues. Conclusion: It could be proved that CHNPs and Ly could synergistically afforded protection against liver injury and oxidative stress as a result of aging. Consequently, CHNPs was an effective agent in the drug delivery in liver diseases medications. CHNP-s and Ly enhanced liver enzymes and improved their antioxidant capacities in liver.