Background: Toxoplasma gondii is an obligate intracellular protozoan that cause the infectious disease toxoplasmosis. Currently, no effective vaccine exists against this parasite for humans. Therefore, this study aimed to evaluate the efficacy of different vaccine candidates including, excreted/ secreted antigens (ESAs), alum-adjuvanted ESAs, mannose-modified nanoliposomes of ESAs, and mannose-modified nanoliposomes of ESAs with alum against acute T. gondii (RH strain) infection in BALB/c mice. Methods: This study started with the preparation of ESAs, and mannose-modified nanoliposomes of ESAs and mice were then immunized separately. Their anti-Toxoplasma antibody and iNOS levels in serum were then measured using ELISA before challenging infection. Subsequently, mice were challenged with T. gondii tachyzoites. Afterward, we assessed the peritoneal fluid's burden of the parasite, survival time, serological anti-Toxoplasma IgG antibodies and iNOS levels, and histopathology of liver and spleen. Results: The vaccinated groups with either alum adjuvanted ESAs or mannose-modified nanoliposome adjuvanted ESAs showed significant reduction in tachyzoites counts and prolonged survival time in a dose-dependent manner. Additionally, there was a significant increase in both anti-Toxoplasma IgG and iNOS levels (P<0.001). Furthermore, there was a considerable reduction in the hepatic and splenic pathological alterations, along with fewer numbers of the parasite than mice received ESAs alone. Notably, vaccination with mannose-modified nanoliposome ESAs yielded more promising results compared to alum-adjuvanted ESAs. Conclusions: mannose-modified nanoliposome may be regarded as an appropriate adjuvant and antigen vehicle system for vaccination against Toxoplasma.