Objective: High glucose (HG)-induced oxidative stress is a metabolic stimulus for hepatic impairment in diabetes. Natural phytochemicals may alleviate HG-induced complications. We aimed to examine the impact of CITRONELLOL (CT) on oxidative stress and inflammation in the human hepatocellular liver carcinoma (HepG2) cell line under HG conditions.Materials and Methods: In this experimental study, the HepG2 cells were exposed to HG concentrations of 50 mM and co-treated with or without CT at concentrations of 10, 20, and 40 μg/ml for 48 hours. The impact of treatments on the levels of malondialdehyde (MDA), glutathione (GSH), and the enzyme’s activity of glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) was explored. We used quantitative reverse transcription polymerase chain reaction (qRTPCR) to evaluate the gene expression of nuclear factor-κβ (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and dipeptidyl peptidase-4 (DPP-4).Results: Co-treatment with CT (20 and 40 μg/ml) significantly reduced (P<0.05) HG-induced cell death (9.73 and 10.56%, respectively) and MDA production (16 and 26.78%, respectively) compared to untreated HG control group. Meanwhile, CT (10, 20, and 40 μg/ml) substantially increased (P<0.05) GSH content (35.61, 55.24, and 69.75%, respectively), GPx (48.32, 61.75, and 75.10%, respectively), and CAT activity (20.25, 25.09, 30.16%, respectively) dose-dependently comparison to untreated ones. TNF-α and IL-6 gene expression were also modulated significantly (P<0.05) by 40 μg/ml CT (47.75 and 32.44%, respectively) as compared to the HG control group. Moreover, CT at 20 and 40 μg/ml attenuated (P<0.05) NF-κB gene expression (30.41 and 39.93%, respectively), and at all doses, made a considerable reduction (P<0.05) in DPP-4 gene expression (18.77, 18.78, and 44.61%, respectively) dose-dependently comparison to untreated ones.Conclusion: Our research suggested that CT with greater effectiveness at 40 μg/ml might shield hepatocytes exposed to HG by lowering oxidative stress and inhibiting inflammatory reactions; however, more research is needed.