Objectives: Liver disease is a serious public health problem. There are many causes of liver disease and the liver is a vital organ in the body, so when it is damaged, its function can be affected. Cochlospermum tinctorium is a plant commonly used by Central African populations to relieve liver-related ailments such as jaundice and hepatitis. This study aimed to assess the hepatoprotective activity of aqueous leafy stem extract of C. tinctorium against liver injury induced by subacute exposure of rats to carbon tetrachloride (CCl4). Material and Methods: Thirty rats were distributed into six groups including control (H2O), healthy control (H2O), positive control (silymarin 25 mg/kg), extract control (aqueous leafy stem extract 50 mg/kg), and tests (aqueous leafy stem extract 50 or 25 mg/kg). Liver injury was induced by CCl4 (0.5 mL/kg) on the 4th and 11th days of the treatment. Rats were sacrificed on the 15th day, aspartate aminotransferase, alanine aminotransferase (ALT), gamma-glutamyltransferase (γ-GT) activity, and serum levels of total bilirubin, creatinine, and tissue oxidative stress markers (malondialdehyde, glutathione, catalase, and superoxide dismutase) were evaluated. Histological examinations of the liver and kidney were performed. A phytochemical study of C. tinctorium aqueous leafy stem extract was done. Results: This study showed that C. tinctorium aqueous leafy stem extract (50 or 25 mg/kg) significantly reduced (P < 0.01) ALT (94.79 ± 14.99 U/L) and γ-GT (10.08 ± 5.40 U/L) activity, and decreased the serum total bilirubin level compared to control. The aqueous leafy stem extract significantly diminished (P < 0.01) tissue MDA level (2.67 ± 0.05 µmol/mg protein), increased glutathione level (347.08 ± 10.81 nmol/mg protein), catalase (131.03 ± 6.99 µmol/ min/mg protein), and SOD activity (86.0 ±1.50 U/mg). Liver microphotography showed hepatic parenchyma with almost no leukocyte infiltration in the portal and perisinusoidal spaces, and an important reduction of cell necrosis following treatment with the aqueous leafy stem extract compared to the control. Conclusion: These results demonstrate that the hepatoprotective activity of the aqueous leafy stem extract of C. tinctorium may be due to its antioxidant and anti-inflammatory properties and may, therefore, justify the use of this plant as a candidate for complementary study to proceed with the development of medicine against liver diseases.