Elephantopus mollis (EM) is a wild species and is commonly used in folk medicine as remedy for various ailments. Some uses of this plant has been documented in the scientific literature. However, studies on the medicinal properties of this specie remain rarely published and the specie has not been recorded in the Vietnamese pharmacopeia. The present study therefore assessed the acute toxicity and liver-protective effects of Elephantopus mollis (EM). The acute toxicity of the aqueous extract of EM in mice was assessed following the method stipulated by the Organization for Economic Cooperation and Development (OECD), while the hepatoprotective effect was assessed following previously reported method. Whole plant extract of EM was not toxic to the tested mice (at a dose of 9,000 mg/kg) and showed good liver protection. The plant extract had the ability to reduce the degradation of liver cells by reducing the amount of liver enzymes. At a dose of 400 mg/kg EM, the reduction efficiency of AST and ALT in tested mice were 71.43 ± 11.36% and 63.82 ± 19.43%, respectively, when compared with the negative control group after 2 weeks of treatment. Mice liver morphology and histopathology treated with EM extract showed a decent improvement. The liver cells size of mice treated with EM extract decreased significantly (28.02 ± 6.33 µm) compared to the mice in the negative control group (34.82 ± 6.36 µm). The results suggest the potential effect of this extract as a hepatoprotective agent towards liver damage without any oral acute toxicity effect.