Currently, the control and treatment of African trypanosomiasis are limited by the number of chemotherapeutic drugs with associated side effects. Consequently, there is an urgent need for a non-toxic herbal treatment for African trypanosomiasis. Leaf, stem, and root bark extracts of Acacia nilotica L. and Guiera senegalensis J. F. Gmel and Ziziphus abyssinica Hochst ex A. Rich were sequentially extracted using hexane, ethyl acetate, methanol and water as solvents and evaluated for in vitro anti-trypanosomal activities against Trypanosoma brucei, and phytochemical contents. Results revealed that out of the 36 extracts, Methanol leaf extracts of G. senegalensis, aqueous leaf extract of G. senegalensis, methanol leaf extract of A. nilotica and methanol leaf extract of Z. abyssinica leaf extract (MIC 3.93±2.88, 10.98±3.21, 16.91±3.21 and 18.88±3.44 μg/ml respectively), gave the best in vitro anti-trypanosomal activity against T. b. brucei compare to the control. The quantitative phytochemical analysis of the 4 most trypanocidal plant extracts revealed the presence of alkaloids, flavonoids, terpene, quinines, saponins and tannins, with alkaloids and flavonoids having the highest concentrations (4.3.13±0.05 mg/100 g and 4.5±0.02 mg/100 g respectively) in the methanol leaf extract of G. senegalensis and quinone with the lowest concentration (0.1±0.07 mg/100 g).The methanol leaf extracts of G. senegalensis were found to have the most in vitro anti-trypanosomal activities (MIC of 3.93±2.88 ug/ml), possibly due to the high content of alkaloids and flavonoids. The results of this study revealed the potential of G. senegalensis for the treatment of African trypanosomiasis. Consequently, further studies are needed with this plant to evaluate its in vivo anti-trypanosomal potential, the structures of the bioactive compounds responsible for its activity, and its other medicinal properties.