Context: The resistance of Plasmodium species to many available antimalarials calls for a continuous search for newer antimalarial agents. One possible source of new antimalarials is from natural sources such as Fagara zanthoxyloides Lam (Rutaceae), a medicinal plant used traditionally for treating malaria in South-Eastern Nigeria, Uganda and Asia. Objectives: To investigate the application of methanol extracts of F. zanthoxyloides in combating malaria infection and its associated disorders. Materials and methods: Methanol extracts of F. zanthoxyloides leaves (MEFZ) were evaluated for in vivo antimalarial activity. MEFZ at doses of 200, 400, and 600 mg/kg/d were administered orally for 4 consecutive days (days 0–4) to P. berghei-infected mice. The possible ameliorative effects of MEFZ on malaria-associated organ malfunctions were also assessed. Results: At 200, 400 and 600 mg/kg b.w., respectively, MEFZ produced 82.37% and 68.39%, 84.84%, and 90.75%, 95.95% and 92.67% chemosuppression and inhibition of P. berghei, respectively, comparable to 98.67% and 97.29% by combisunate, a standard antimalarial. The IC50 of MEFZ was estimated to be 235.23 mg/kg b.w. Similarly, treatment of parasitized mice with MEFZ significantly restored the malaria-modified haematological and biochemical status of the parasitized-MEFZ-treated mice compared with parasitized-untreated mice. MEFZ was tolerable up to 5000 mg/kg b.w dose; hence, the LD50 is above 5000 mg/kg b.w. Discussion and conclusions: The results of this curative assay demonstrated that MEFZ has antimalarial effects and normalized haematological and biochemical aberrations generated by malaria. The isolation of the antimalarial principles in MEFZ is warranted; they could be lead molecules for the development of new antimalarials.