Background: Hepatocellular carcinoma (HCC), one of the most common cancers in the world, is a leading cause of cancer-related mortality. Resveratrol (RSV) and Baicalein (BE) are naturally derived polyphenolic compounds showed promising chemo-preventive effects against cancer. Aim: The present study aims to investigate the antioxidant activity of RSV and/or BE against induced HCC in rats. Methods: 48 Swiss male adult albino rats were divided into 6 groups: Group I served as a negative control injected intraperitoneally (I.P) with sterile saline; Group II were injected I.P with (0.25%) Dimethylsulphoxide (DMSO); Group III were injected I.P with Diethylnitrosamine (DEN) (200 mg/kg.bw) once; Group IV injected by DEN then treated with BE (20 mg/kg.bw) I.P for 10 consecutive days; Group V injected by DEN then treated with RSV (2.5 mg/kg.bw) orally for consecutive 10 days; Group VI injected by DEN then treated with BE and RSV. Plasma was collected for some biochemical studies and different antioxidant assays. Results: DEN-induced HCC that manifested by a significant drop in antioxidants levels, alterations in liver functions, and induced- inflammation. While, treatment with RSV and/or BE ameliorated liver injury by decreasing (alanine transferase (ALT), aspartate transferase (AST) activities, and Galectin-3 (Gal-3) levels. Also, they reversed the oxidative stress by the reduction of malondialdehyde (MDA) and nitric oxide (NO) levels and restoration of superoxide dismutase (SOD), glutathione-S-transferase (GST) activities, and reduced glutathione (GSH) levels. They decreased interlukin-6 (IL-6) levels. These data suggested that RSV or BE exhibited a significant role against HCC, which  might be related to their antioxidant and anti-inflammatory activities. Conclusions: Although combined treatment with RSV and BE significantly exerting a potential therapeutic effects, individual administration was more effective in HCC treatment. These novel findings suggested that RSV and BE have an antagonistic effect suggesting concerted efforts are needed to identify the most optimal combinatorial strategies.