Jatropha curcas is used as an old herbal therapy in the treatment of several vector-borne diseases in several parts of Africa. Considering the burden of trypanosoma infection and the cost of currently available drugs, the search for more drugs that are effective, affordable and accessible is warranted. To investigate the anti-trypanosoma and ameliorative effects of ethanol extracts of Jatropha curcas root (EEJCR) on organ malfunctions associated with trypanosoma infection in rats, and its phytoconstituents and acute toxicity profile. Thirty rats were divided into six groups of rats (n = 5): nonparasitized rats in group 1 served as normal control and parasitized (1.8 × 106 trypanosomes/ml of Trypanosoma brucei brucei–infected blood) rats in group 2 served as trypanosome control. Parasitized rats in group 3 were treated with reference drug (diminazene aceturate) while groups 4–6 were treated with 100, 200 and 400 mg/kg/day b.w. p.o. of EEJCR, respectively for 7 days. The acute toxicity profile of EEJCR was established in mice using the standard method. In a dose-dependent fashion, EEJCR reduced trypanosoma parasitaemia; 400 mg/kg/day b.w. of EEJCR gave 82.96% chemosuppression compared with 100% by diminazene aceturate. EEJCR also ameliorated trypanosoma-modified haematological and biochemical dysfunctions in a dose-related manner. The presence of tannins, steroids, flavonoids, terpenoids, phenols, glycosides and alkaloids was detected in EEJCR and it was tolerable up to 5000 mg/kg b.w. This study showed that EEJCR is safe, has anti-trypanosoma activity and reverses haematological and biochemical markers of organ malfunctions associated with trypanosoma infection. This observation justifies the old routine use of such herbal therapy in medicinal practices to treat trypanosomiasis. © 2020, Springer-Verlag London Ltd., part of Springer Nature.