Objective: To examine the effect of coadministration of different medicinal plant extracts (curcumin and extracts of Nigella sativa L. [N. sativa, Jia Hei Zhong Cao], Zingiber officinale Rosc. [Z. officinale, Sheng Jiang], and Punica granatum L. [P. granatum, Shi Liu]) with spiramycin (SP) against the cystogenic ME-49 Toxoplasma gondii (T. gondii) strain in immunocompromised mice. Methods: We utilized 68 mice categorized into 8 groups: 2 non-infected controls (immunocompetent and immunocompromised), 1 infected control, and 5 infected and treated groups. Following the experiment, the cerebral tissues of each mouse underwent parasitological, histopathological, and immunohistochemical evaluations. Results: Compared with the infected non-treated group, all infected treated groups showed significant reductions in brain cyst numbers (all P < .05), with the highest reduction rate (77.4%) recorded for P. granatum and SP combination (G8). Only G8 showed a significant reduction in mouse deaths compared with the other groups. With regards to restoring histopathological changes and decreasing inflammation, the groups infected and treated with curcumin and P. granatum combined with SP showed the best results (P < .05). Combinations of curcumin and extracts of Z. officinale and P. granatum with SP significantly restored the cerebral expression of caspase-3 compared with the N. sativa extract combination (P < .05). G8 showed non-significant expression compared with the local expression in the negative control groups. Conclusion Our study revealed that the coadministration of P. granatum extract with SP was the most effective combination against chronic cerebral toxoplasmosis.