The utilization of mesenchymal stem cells (MSCs) serves as an encouraging strategy for treating liver fibrosis. However, precise mechanisms are not completely understood. Recently, small extracellular vesicles (sEVs) have emerged as major paracrine effectors mediating the anti-fibrotic effects of MSCs. This study seeks to examine the healing properties of MSCs-sEVs on liver fibrosis and decipher the associated signaling pathways. Herein, MSCs substantially ameliorated carbon tetrachloride (CCL4)-induced liver inflammation and fibrosis in mice, with this effect predominantly attributed to their derived sEVs. Both in vivo and in vitro experiments verified that MSCs-sEVs skewed the phenotype of liver macrophages into an anti-fibrotic phenotype. Mass spectrometry analysis showed that ubiquitin-specific peptidase 10 (USP10) was significantly enriched in MSCs-sEVs, which was critical for protection against liver fibrosis. USP10 stabilizes Krüppel-like factor 4 (KLF4) via deubiquitination, participating in the modulation of macrophage phenotypes. Mechanistically, KLF4 reprograms macrophages to enhance their anti-inflammatory and repairing functions by modulating NF-κB/STAT6 signaling and regulating the transcription of MMP12. Finally, the exogenous incorporation of USP10 into MSCs-sEVs via genetic engineering further potentiated their antifibrotic effects. These findings deepen the knowledge regarding the cellular pathways through which MSCs ameliorate liver fibrosis, offering a theoretical basis for sEV-based therapeutic strategies.