African animal trypanosomiasis is one of the most important protozoal diseases affecting animal health and production. This study was conducted to assess the phytochemical composition of Phyllanthus amarus ethanol extract and to assess its safety and efficacy on Trypanosoma brucei-induced pathology in Wistar rats. The plant sample was obtained from around the residential area in Ahmadu Bello University, main campus, Zaria, Nigeria, and subjected to phytochemical screening following standard procedures. Sixteen Wistar rats were divided into five groups, each rat in the groups receiving 0.1 mL of 10⁶ T. brucei trypomastigotes. After three days of patency, rats in groups III to V were given different plant extract treatments for four days, while rats in groups I and II served as negative and positive controls. Following treatment, clinical parameters, parasitaemia, gross pathology and biochemical analysis were observed and recorded. The results showed that the ethanol extract contained primary constituents such as alkaloids, phenols, cardiac glycosides, saponins, carbohydrates, triterpenes, anthraquinones, tannins, and steroids. The extract was found to be non-toxic and orally safe for Wistar rats. It showed moderate suppressive ability against parasitaemia, ameliorating fever, weight loss, and anaemia in Trypanosoma brucei-infected rats. It also demonstrated significant modulatory activity in reducing internal organ pathologies, liver enzyme pathology, and oxidative stress in the heart, kidney, and spleen. The study highlights the safety and efficacy of Phyllanthus amarus ethanol extract in managing African animal trypanosomiasis.