ABSTRACT Background: The search for alternative trypanocidal compounds which can be available at affordable price is of paramount importance for control of trypanosomosis in human and animals. The current study evaluates the in vivoactivity of ethanolic stem bark extracts on Trypanosoma congolense and selected immunological components in aninbred Swiss albino mouse model. Methods: Groups of mice infected with T. congolense were treated with the stem bark extracts at a rate of 1000 mg/kg,1500 mg/kg, and 2000 mg/kg, twice a day in one set and thrice a day in another setting for three days consecutively.Negative (infected and untreated) and positive (infected treated with diminazene diaceturate at 3.5 mg/kg) control groups were used. Levels of parasitaemia were monitored daily for the first 10 days and thereafter 2–3 times per week to the end of experiment. In the other setting, uninfected mice, randomized in groups were treated with the extract but categorized as: thorough mixed extract (TME) and supernatant extract (SE) each at 500 mg/kg and 1500 mg/kg, in 8 hourly intervals respectively for three days consecutively. Control group was administered with phosphate buffered saline with glucose at 0.1 ml/10 g in a similar manner as for the extract. Whole blood and spleen were taken 24 h after the last treatment for hematological and histopathological analysis. Results: The groups that received the extracts at 8 hourly intervals drastically reduced the parasitaemia. The higher dose of SE significantly reduced the percentage of lymphocytes (P < 0.05). Both high and low dose of TME significantly reduced lymphocytes percent (P < 0.05) while percent of neutrophils and monocytes increased significantly (P < 0.05). Histopathological changes of the spleen in the mice treated with higher concentrations of the extract of C. swynnertonii were suggestive of lymphocytes toxicity. Conclusion: The current study has provided evidence that, in vivo trypanocidal activity of ethanolic bark extracts of C.swynnertonii is probably affected by its negative effect on humoral mediated immune response. Further studies are recommended to determine its potential as an alternative source of lead compounds for trypanocidal drug discovery