Background: Although several drugs and natural products were investigated in the treatment of chronic toxoplasmosis, brain cysts are still resistant to eradication. Objective: To evaluate the immunomodulatory effect of Nigella sativa oil (NSO) and wheat germ oil (WGO) loaded metal-organic frameworks (MOF) on mice with chronic toxoplasmosis. Material and Methods: Eighty male Swiss albino mice were divided into 8 groups (10 mice each); GI: non-infected non treated, GII-GVIII: infected with ME-49 avirulent strain of T. gondii; GII: non-treated, GIII-GVIII were treated with Spiramycin (GIII), Spiramycin-MOF (GIV), MOF (GV), WGO-MOF (GVI), NSO-MOF (GVII), and WGO+NSO-MOF (GVIII). Immunological evaluation was performed through immunohistochemical (IHC) staining of liver sections, and serological detection of immunological markers, i.e., interferon-gamma (INF–γ), and tumor necrosis factor-alpha (TNF–α). Results: IHC examination revealed a high predominance of CD8+ cells elicited in GVII, and GVIII followed by GVI. A statistically significant difference was recorded between the treated test and control groups regarding the levels of INF–γ, and TNF–α in their sera with the highest level recorded in GVII followed by GVIII, GVI, GIII, GIV, and GV, respectively. Conclusion: Our study showed that NSO and WGO combinations with MOF exhibited significant immunostimulant effects against chronic murine toxoplasmosis.