Background and aim: Hydroxyurea (HU) possesses several characteristics of an ideal drug for various diseases, despite the reported side effects. The current study intends to search for the potential ameliorative effectiveness of vitamin C on hydroxyurea-induced hepatotoxicity in a rat model. Materials and methods: 24 adult male albino rats were split into four groups. Group I served as the control; Group II received 5 mg/kg bw of vitamin C; Group III received 100 mg/kg bw of HU; and Group IV received a combination of 5 mg/kg bw VC and 100 mg/kg bw HU, which were administered orally for 30 days to assess liver function tests, oxidative stress, histopathology, and the detection of DNA damage. Results: The results demonstrated a significant decline (p < 0.01) in the absolute organ weight of rats treated with HU. However, there was no significant contrast in the liver-relative condition. The rats exhibited elevated levels of AST, ALT, and MDA a reduction in albumin, total protein, SOD, CAT, and GSH. The group that received HU displayed signs of degeneration, hydropic deterioration, and fatty degeneration. A comet assay revealed an increase in tail length and DNA content in liver cells. There was no significant difference in olive tail moment but a significant decrease in % tailed, % DNA in the tail, and tail moment. Conclusion: The administration of VC with HU improved liver function tests, oxidative stress, and histopathology compared to the HU group.