Toxoplasma gondii infection remains a significant global health concern, promoting the urgent need for effective therapeutic strategies. This study aimed to evaluate the therapeutic potential of chitosan nanoparticles (CSNPs) and curcumin-loaded chitosan nanoparticles (Cur-CSNPs) against the chronic Toxoplasma gondii (ME49 strain) in an experimental mouse model. This achieved by investigating their ability to reduce parasitic load, oxidative stress, histopathological lesion, and to enhance the host immune response. Sixty female BALB/c mice were divided into five groups: infected untreated group, Spiramycin®-treated group, CSNPs-treated group, Cur-CSNPs-treated group, and negative control group. The Cur-CSNPs-treated group exhibited the lowest brain cyst counts, along with significant reductions in cyst size. Hematological indices revealed no significant reduction in total white blood cell (WBC) counts or in the percentage of neutrophils, monocytes, and eosinophils in both the CSNPs and Cur-CSNPs treated groups, compared to the infected untreated group and Spiramycin-treated group. However, both nanoparticle-treated groups exhibited a significant decrease in the percentage of lymphocytes compared to the infected untreated group. Significant differences in total antioxidant capacity (TAC) and malondialdehyde (MDA) levels were observed, with the Cur-CSNPs treated group displaying values comparable to the negative control. Histopathological examination revealed substantial improvements in the brain, liver, and spleen tissues of Cur-CSNPstreated animals, characterized by preserved tissue architecture and reduced inflammatory lesions. Immunohistochemical analysis further revealed reduced expression of IL-6 and TNF-α, indicating a mitigated inflammatory response. These findings highlight the promising therapeutic role of CurCSNPs in controlling chronic T. gondii infection and suggest their potential as a novel strategy for developing effective antiparasitic treatments.