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This study investigated a 'de Novo' medicinal herb, Ferula asafetida (FA), against toxoplasma encephalitis either alone or combined with spiramycin (SP). Female Swiss‐Webster mice (n = 72) were divided into three batches. Batch‐I received no DMS to serve as an immunocompetent control, batch‐II was immune‐suppressed with the DMS (0.25 mg/g/day) for 14 days pre‐infection, whilst batch‐III was immune‐suppressed with the DMS on the same day of infection. All experimental mice were inoculated with Toxoplasma gondii ME49 cysts (n = 75). Each batch was split into four subgroups: Mono‐SP, mono‐FA, combined drug (SP + FA), or neither. Therapies were administered on day zero of infection in batches (I and II) and 35 days post‐infection in batch (III). Treatments lasted for 14 days, and mice were sacrificed 60 days post‐infection. Histopathological changes, cysts load, and CD4 and CD8 T‐cells were counted in brain tissues. The cyst‐load count in mice receiving SP + FA was significantly (p <.0001) the least compared to the mono treatments in all protocols. Interestingly, the combined therapy demolished the T‐cell subsets to zero in immunocompetent and immunocompromised infected mice. In conclusion, F. asafetida might be a powerfully natural, safe vehicle of SP in the digestive system and/or across the brain–blood barrier to control toxoplasmosis even through immunodeficient conditions. [ABSTRACT FROM AUTHOR]