The understanding of medulloblastoma (MB) progression is limited by the lack of minimally invasive monitoring methods. Extracellular vesicles (EVs) carrying disease-specific signatures are promising for liquid biopsies, but clinical translation is hindered by inconsistent isolation techniques. This study compares small EVs (sEVs) and their proteomes from blood plasma (BP) and cerebrospinal fluid (CSF) in MB. Using ultrafiltration and size exclusion chromatography (UF-SEC), we isolated sEVs from pediatric patient samples. sEV proteins from matched CSF-BP samples from MB patients (MBCSF/MBBP), healthy BP controls (HCBP), and MB cell lines (MBCL) were analyzed by liquid chromatography-tandem mass spectrometry, subjected to Gene Ontology and Cytoscape analyses, and compared to published MB, CSF, and EV datasets. By optimizing UF-SEC for small volumes, we found that CSF-sEVs are smaller and elute in later SEC fractions. Proteins linked to the extracellular matrix (ECM) were enriched in MBCSF and MBCL, while integrin binding showed inconsistent patterns between MBCSF and MBBP. MBBP and HCBP showed no significant differences. Fourteen proteins from MB datasets were identified in our analysis and primarily enriched in CSF. These findings support CSF-sEVs as more informative than BP-sEVs for MB diagnosis and monitoring, emphasize the need for fluid-specific sEV isolation, and suggest that ECM components and integrins may mediate MB progression.