Background: Hepatocellular Carcinoma (HCC) being proclaimed as the world's fifth common cancer shows a high mortality rate due to delayed diagnosis. Regular day-to-day activities expose us to promotive factors that potentiate further to risk of liver damage, cirrhosis, and carcinogenesis. Matrix metalloproteinases (MMPs), a proteolytic enzyme, involved in cancer invasion are considered as a prognostic biomarker for HCC. Naringin (NAR), a flavanone glycoside, is recognized to have therapeutic efficacy in HCC. Objectives: The present research work focuses on evaluation of chemotherapeutic efficiency, NAR against HCC in Sprague–Dawley rats. Materials and Methods: In vitro studies were primarily carried out to estimate the cell viability of NAR in HepG2 cells followed by further justifications through in vivo studies in N-nitrosodiethylamine developed HCC. The efficacy of NAR at doses 30mg/kg/day and 60mg/kg/day was assessed through estimation of liver marker enzymes, antioxidant levels, glycoproteins, and level of MMP-2 and 9 to confirm the hypothesis. Results: While in vitro results revealed pronounced potency of NAR in inhibiting HepG2 cell viability, NAR concurrently stabilized the serum levels of liver marker enzymes, antioxidant levels, and serum glycoproteins. It also significantly reduced the levels of MMPs in treatment groups which was confirmed by zymography. Conclusion: With the support of these results, it can be concluded that NAR attenuates HCC by controlling the alterations in morphological, biochemical, and histopathological parameters that make it a suitable candidate as a potential chemotherapeutic agent against HCC.