Background: Syringodium isoetifolium seagrass has bioactive constituents with potential pharmacological uses, but their use is limited owing to scarce scientific evidence. The in vivo anti-cancer activity of Syringodium isoetifolium against DEN-induced hepatocellular carcinoma in Wistar albino rats is described in this work for the first time. Materials and methods: Wistar albino rats were used as test subjects to examine the anti-cancer properties of Syringodium isoetifolium against DEN-induced hepatocellular carcinoma at the dose of 50 mg/kg body weight. The experimental rats were split into five groups (Group I-V). Except for group I, remaining all animals received DEN and Phenobarbitone during the experiment. Group I and Group II acted as normal and diseased control groups respectively. The extracts were administered to the satellite group III and IV orally with the dose of 250 and 500 mg/kg body weight respectively. 5 fluorouracil 20mg/ kg was administered to group V orally and considered as a standard. The total experimental period lasted for 14 weeks. Results:The findings show that Syringodium isoetifolium significantly reduces liver tumor volume, burden and numbers in experimental rats (p<0.05) when compared to the control group. Besides, the extracts treated groups restored the pathological parameters close to normal values (p<0.05). The histological analysis also showed that the extract-treated animals' livers had recovered their normal architecture. Conclusion: The study concludes that Syringodium isoetifolium inhibits the cancer growth in hepatocellular carcinoma by altering the antioxidant defense system, glycolysis and protecting the membrane architecture by inhibiting the elevated levels of haematological, biochemical parameters and biomarker values.