The present study aimed to investigate the therapeutic potential of the methanolic extract of Lepidium sativum seeds in mice experimentally infected with Trypanosoma evansi. A total of thirty-two male Swiss albino mice were randomly divided into four groups: the first group was the normal control, while the second, third and fourth groups were infected intraperitoneally with 1 × 104 trypanosomes. The third and fourth groups were treated with 100 μl of Lepidium sativum seed extract (LSSE) at a dose of 200 mg/kg body weight intraperitoneally (infected + LSSEI) and orally (infected + LSSEO) respectively, once a day, for a period of four days.Parasitaemia was found to be significantly raised in the untreated infected group, reaching 2 × 107 at day 4 post-infection, but was significantly reduced by 65.5% and 88% in the mice treated orally and intraperitoneally with LSSE, respectively. The erythrocyte count, HCT, haemoglobin content, leucocyte count and the percentage of lymphocytes was significantly reduced in the untreated infected group, while the treatment with LSSE returned these parameters to their pre-infection values. In addition, our study proved that LSSE provided protection against liver tissue damage and decreased the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The present study also established that intraperitoneal injection of LSSE is more effective than oral administration in the treatment of trypanosome infection in mice. In conclusion, the infection caused haematological, biochemical and histological changes that were ameliorated following treatment with LSSE.