Microglia are the resident immune cells of the central nervous system and play a vital role in cytoprotection by maintaining brain homeostasis via direct interaction and/or secretion of molecules and vesicles with neurons, other brain cells, and even themselves. Extracellular vesicles are involved in cell-to-cell communication by transporting bioactive molecules, such as miRNAs, to recipient cells. microRNAs (miRNAs) are small noncoding RNAs that contribute to gene expression by silencing mRNAs, and it has been demonstrated that the content of the small extracellular vesicles includes miRNAs. In this study, we aimed to investigate the cytoprotective function of IL-4-induced microglia-derived small extracellular vesicles (IL-4 sEVs) on LPS-induced damage in microglia. The reason for this study is to examine the cytoprotective effects of small extracellular vesicles on LPS-induced microglial damage. For this purpose, microglia cells were treated with IL-4 and sEVs were isolated by ultracentrifugation. miRNA content of IL-4 sEVs was profiled by small RNA sequencing. We found that hsa-miR-191-5p levels were significantly increased in IL-4 sEVs, and upregulation of hsa-miR-191-5p levels was confirmed in IL-4 sEVs. Furthermore, IL-4 sEVs were taken up by microglia and ameliorated LPS-induced damage in vitro. In addition, we showed that hsa-miR-191-5p in IL-4 sEVs attenuated LPS-induced damage by reducing cytokine secretion and cell death. In conclusion, these results suggest that IL-4 sEVs ameliorate LPS-induced damage via hsa-miR-191-5p in microglia. This study opens up new possibilities for developing therapeutic strategies for LPS-induced microglial damage using IL-4 sEVs.