Background: Burkina Faso is classified among the countries with a high prevalence (˃12%) of hepatitis. Hepatic diseases, such as cirrhosis—related to alcoholism—and hepatitis B and C, are the cause of the increase in cases of liver cancer. They promote the development of cancer by decreasing the natural cell death, causing problems with DNA repair, or by increasing the production of free radical toxins to the cell. According to the World Health Organization (WHO), there were nearly 639,000 deaths from liver cancer worldwide in 2014, hence the need to search for natural hepatoprotective molecules. Objective: To evaluate the hepatoprotective potential of Acanthospermum hispidum extracts on rats and the antioxidant capacity of extracts in vitro and in vivo, and to perform phytochemistry. Methods: The ethanolic and aqueous extracts of the whole Acanthospermum hispidum plant were used to evaluate hepatoprotection. The hepatotoxin used in our case was diethylenitrosamine. The animals were divided into groups of six. The sera of the treated animals were used for the determination of transaminases, and the liver homogenates were used for the determination of antioxidant. The total phenol and flavonoid contents, and the antioxidant properties of the extracts, were evaluated in vitro. Results: The results of the in vitro antioxidant tests showed good antioxidant activity of the ethanolic extract, using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) test (0.08 ± 0.0018 μg/mL) and 2,2′-azinobis (3-ethylbenzolin-6-sulphonate) (ABTS) (246.05 ± 1.55 mmol TE/g). The in vivo tests showed, through the evaluation of the antioxidant in vivo and the biochemical parameters, that the ethanolic extract with the highest phenolic content had a good hepatoprotective capacity. Conclusions: The antioxidant activity of Acanthopermum hispidum extracts would justify the observed hepatoprotective activity. These results confirmed that the plant is used in the treatment of liver diseases in traditional medicine in Burkina Faso.