One of the leading causes of death worldwide, cirrhosis, is a liver condition characterized by chronic necrosis, inflammation, and fibrosis. Hepatoprotective compounds, such as antioxidants, can prevent fibrosis. Macroalgae (seaweed) contain high amounts of antioxidant compounds and are plentiful; indeed, species such as Sargassum fluitans Borgesen (Phaeophyceae) carpet many beaches in the Caribbean Basin. An in vivo assay was done evaluating the possible hepatoprotective effect of a Sargassum fluitans ethanol extract. Two murine liver damage models were employed: acetaminophen (APAP) in Balb/c mice to induce acute damage; carbon tetrachloride (CCl4) in Wistar rats to induce chronic damage. Serum liver enzyme levels and relative liver weight were measured, and histopathological and immunohistochemical analyses of liver tissue sections were done. Both APAP and CCl4 significantly raised serum enzyme marker enzymes. Administration of 50 mg/kg S. Fluitans ethanol extract reduced this APAP- and CCl4-induced elevation to normal levels. This effect was corroborated by the extract's inhibition of inflammation and fibrosis in liver tissue observed in the histopathological analysis. The analyzed S. fluitans ethanol extract exhibited an in vivo hepatoprotective effect in acute and chronic liver injury models.