<p>The modulation of microglial reactivity has emerged as a potential target for developing ischemic stroke therapies. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) possess immunomodulatory properties that may influence microglial responses following ischemia. However, individual studies assessing this influence have provided limited results. Therefore, we conducted a systematic review and meta-analysis to investigate whether MSC-EVs treatment alters microglial responses in animal and cellular models of ischemic stroke. In accordance with the PRISMA 2020 statement, we searched PubMed, Web of Science, and EMBASE until January 2025 for studies assessing cellular and molecular parameters of microglial reactivity following MSC-EVs treatment in models of ischemic stroke. We estimated treatment effects using a random-effects meta-analysis of standardized mean differences and estimated heterogeneity via the <i>I</i>² statistic. The risk of bias was assessed using the SYRCLE questionnaire. The search identified 386 studies, 35 of which met the inclusion criteria. In animal models, MSC-EVs reduced the number, surface area, and fluorescence intensity of Iba1⁺ cells, as well as the number of Iba1⁺ cells co-expressing the pro-inflammatory markers CD16, CD32, CD85, and iNOS. Conversely, MSC-EVs increased the number of Iba1⁺ cells co-expressing the anti-inflammatory markers Arg-1 and CD206. In cellular models, we observed decreased concentrations of TNF-α, IL-1β, and IL-6 in the culture medium. Our meta-analysis consolidates the immunomodulatory effects of MSC-EVs on microglial responses to ischemia, underscoring the potential of microglia-specific therapeutics in the development of MSC-EVs-based and regenerative treatments for ischemic stroke.</p>