Medicinal plants are used worldwide in folk medicine to treat many diseases, including those affecting the liver, but most of those plants are not yet studied. The present study aimed at the in vivo evaluation of the hepatoprotective potential and doing a preliminary phytochemical screening of Desmodium repandum (Vahl) D.C. leaves ethanolic extract, a plant used in many regions of Africa to treat liver diseases. The presence of main phytochemical groups was assessed by using specific reactions of identification. Hepatoprotective activity was evaluated in male guinea pigs; the hepatotoxicity was induced by oral administration of paracetamol (acetaminophen) at the dose of 500 mg/kg. Silymarin was used as the reference drug at the dose of 100 mg/kg, the control group received a solution of carboxymethylcellulose (CMC) 1%, and the experimental groups 100 and 200 mg of the extract per kg of body weight. The results of phytochemical screening revealed the presence of anthocyanin, phenolic compounds, coumarins, flavonoids, quinones, tannins, sterols, and triterpenes. At the dose of 200 mg/kg, the extract reduced significantly (p ˂ 0.05) the blood concentration of aspartate transaminase (AST), alanine transaminase (ALT), and total bilirubin after intoxication by paracetamol comparatively to the control group. This work demonstrated for the first time the hepatoprotective potential of the ethanolic extract of Desmodium repandum (Vahl) D.C. leaves.