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This study has scientifically validated the most probable principle and site of action in the ethno-medicinal practice for the use of Khaya senegalensis and Tamarindus indica in the treatment of Trypanosomiasis. This may be due to the inhibitory effect of the aqueous extracts of Khaya senegalensis and Tamarindus indica on protein tyrosine phosphatase. Having explored the trypanocidal properties in the plant extracts, the bioactive compounds identified may be effective therapeutic agents for the treatment and management of trypanosomiasis.