The current investigation was carried out to estimate the protective effect of aqueous extract of Cheatomorpha gracilis (AEC) against High fat Diet (HFD) induced liver damage in mice. The results of the in vitro study showed that AEC have higher antioxidant capacities in the DPPH and hydroxyl radical-scavenging assays. Indeed, many phenolic compounds (gallic acid, quercetin, naringenin, apigenin, kaempferol and rutin) were identified in the AEC. In the animal studies, during 6 weeks, HFD promoted oxidative stress with a rise level of malonaldehyde (MDA), protein carbonyls (PCOs) levels and a significant decrease of the antioxidant enzyme activities such as superoxide dismutase, catalase and glutathione peroxidase. Interestingly, the treatment with AEC (250 mg/kg body weight) significantly reduced the effects of HFD disorders on some plasmatic liver biomarkers (AST, ALT and ALP) in addition to, plasmatic proteins inflammatory biomarkers (α2 and β1 decreases / β2 and γ globulins increases). It can be suggest that supplementation of MECG displays high potential to quench free radicals and attenuates high fat diet promoted liver oxidative stress and related disturbances.