Mesenchymal stem cells (MSCs) have therapeutic potential for liver fibrosis, but their efficacy remains variable. Interferon-γ (IFN-γ) priming enhances MSC immunomodulatory properties. However, whether it improves anti-fibrotic efficacy and the underlying mechanisms remain unclear. Here, we investigated the therapeutic effects of IFN-γ-primed MSCs (MSC^IFN-γ) and their extracellular vesicle (EV)-mediated mechanisms. In DDC-induced biliary fibrosis, MSC^IFN-γ showed greater efficacy than naïve MSCs, reducing liver injury, hepatic stellate cell (HSC) activation, extracellular matrix deposition, and inflammation. Secreted protein acidic and rich in cysteine (SPARC), a matricellular protein predominantly expressed by activated HSCs, promotes fibrogenesis and macrophage inflammation through autocrine and paracrine signaling, respectively. Notably, MSC^IFN-γ, but not naïve MSCs, suppressed hepatic SPARC expression. Comparative EV microRNA profiling identified miR-29b-3p as enriched in MSC^IFN-γ-derived EVs. miR-29b-3p directly targeted the SPARC 3′-UTR, and its inhibition abolished EV-mediated suppression of SPARC and fibrotic markers. These effects were reproduced in CCl₄-induced liver fibrosis. Collectively, IFN-γ priming enhances the anti-fibrotic efficacy of MSCs by enriching EV miR-29b-3p, which targets HSC-derived SPARC, identifying the EV-miR-29b-3p/SPARC axis as a mechanism underlying the enhanced therapeutic potency of MSC^IFN-γ.