Objective To explore the immunoprotective effect and mechanism of exosomes derived from Plasmodium-infected red blood cells on experimental cerebral malaria (ECM) in mice. Methods Exosomes were extracted and identified from peripheral blood of BALB/c mice infected with Plasmodium yoelii 17XNL (P.y17XNL). C57BL/6J mice were randomly divided into ECM group, exosome immunization group (Exos + ECM group) and negative control group (NC group). Mice in the Exos + ECM group received two doses of exosome immunization via tail vein injection; 20 days after immunization, mice in the ECM group and Exos + ECM group were intraperitoneally injected with 1 × 10⁶ P. berghei ANKA (P.bANKA)-infected red blood cells, while mice in the NC group were intraperitoneally injected with an equal volume of normal saline. The erythrocyte infection rate and mice survival rate were dynamically observed. Mice brain tissues were collected, and the absorbance at 630 nm (A₆₃₀ value) of the supernatant was detected after Evans blue perfusion to evaluate the integrity of the blood-brain barrier in mice. Hematoxylin-eosin (HE) staining was used to observe the pathological changes of mice brain tissue, and immunohistochemical staining was performed to detect the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in brain microvessels. Western blotting and real-time fluorescent quantitative reverse transcription PCR (qRT-PCR) were used to detect the changes of inflammation-related cytokines in mice brain tissue. Proteomics analysis was combined to explore the regulatory association between core differential components of exosomes and brain tissue inflammatory factors. Results The erythrocyte infection rates of the ECM group and Exos + ECM group reached the peak on day 11 and day 15 post-infection, with values of (25.0 ± 0.0)% and (17.2 ± 4.4)%, respectively, and the erythrocyte infection rate in the Exos + ECM group increased more slowly. All mice in the ECM group died of cerebral malaria on day 13 post-infection, and the survival rate of mice in the Exos + ECM group was 83.3% on day 15 post-infection. The detection results of blood-brain barrier integrity showed that the blood-brain barrier in the ECM group was damaged, while the damage in the Exos + ECM group was not obvious. the A₆₃₀ values of the supernatant in the NC group and Exos + ECM group were (0.28 ± 0.04) and (0.62 ± 0.01) respectively, both lower than (0.89 ± 0.02) in the ECM group (t = 24.24, 10.53, both P < 0.01). The results of HE staining and immunohistochemistry of brain tissue showed that, compared with the ECM group, the number of infected red blood cells in brain microvessels, inflammatory infiltration, and the expression levels of ICAM-1 and VCAM-1 in the Exos + ECM group were reduced. The qRT-PCR results showed that the relative mRNA transcription levels of ICAM-1, VCAM-1, interleukin-6 (IL-6), IL-17A, transforming growth factor-β (TGF-β) and IL-10 in the brain of Exos + ECM group mice were 4.05 ± 0.42, 1.24 ± 0.14, 0.48 ± 0.3, 0.27 ± 0.31, 1.39 ± 0.53 and 4.23 ± 3.29, respectively, which were lower than 8.11 ± 0.86, 2.80 ± 0.33, 1.38 ± 0.76, 2.28 ± 0.26, 2.94 ± 0.49 and 16.02 ± 3.56 in the ECM group (t = 8.76, 8.52, 2.91, 6.81, 4.51, 5.41, P < 0.01, 0.01, 0.05, 0.01, 0.05, 0.01). Western blotting results showed that the protein expression levels of Toll-like receptor 4 (TLR4), IL-1β and tumor necrosis factor-α (TNF-α) in the brain of Exos + ECM group mice were 0.84 ± 0.06, 0.81 ± 0.04 and 2.07 ± 0.72, respectively, which were lower than 1.24 ± 0.04, 0.85 ± 0.03 and 6.06 ± 2.45 in the ECM group (t = 7.07, 1.27, 3.12, all P < 0.05). Proteomics results showed that the differential proteins of exosomes from P.y17XNL-infected mice and normal mice were mainly enriched in nuclear proteins, cytoplasmic proteins, plasma membrane proteins and mitochondrial proteins, which were related to protein export, transport and amino acid metabolism. Conclusion Exosome immunization had an immunoprotective effect on ECM, which can reduce the erythrocyte infection rate and improve the survival rate of mice. The main mechanism may be related to reducing brain inflammation, protecting the integrity of the blood-brain barrier and improving the pathological damage of mice brain tissue.