There is now a greater concern in the marine organisms, especially algae, to find active ingredients to be used as therapeutic drugs in the medical applications. Delivery of drugs into the target organs with high specificity is now achieved when these compounds are coated on nanoparticles which improve the therapeutic properties of anti-tumor products. So, the current investigation aimed to assess the hepatoprotective capacity of silver nanoparticles (AgNPs) prepared by using ethanol extraction of Sargassum muticum (SmAgNPs) versus diethylnitrosamine (DEN) promoted liver tumor in male rats. Swiss albino male rats were allocated into several treated groups. Diethylnitrosamine (DEN, 20 mg per kg body weight) was used for 2 months in male rats to induce liver tumor and then treated with several concentrations (25, 50, and 75 mg per kg body weight) of algae extracts and SmAgNPsas well as with a reference drug (30 mg/kg of Silymarin) for 8 weeks. The results revealed that treatment of DEN-rats with SmAgNPsdecreased levels of the liver function enzymes, namely, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), decreased rates of the DNA damage, and increased activity levels of antioxidant enzymes such as catalase (CAT) and glutathione peroxidase (GPx). Additionally, DEN-rats treated with silver nanoparticles of S. muticum elevated the expression levels of tumor suppressor genes (such as ING3 and Akr1b10) and diminished the levels of oncogene (FoxP1) expression explaining that SmAgNPshas antitumor activity through alteration of the liver cancer-related genes. The results concluded that the high competence of S. muticum nanoparticles for protecting the DNA from damage and increase the antioxidant activities as well as enhance the up-regulation of tumor suppressor mRNAs is attributed to its rich active compounds of fucoxanthin (as marine carotenoids) and fucosterol (marine sterol).