Peritoneal fibrosis is a complication of long-term peritoneal dialysis (PD) that restricts its clinical application for the treatment of end-stage renal disease. Lactobacillus casei Zhang (LCZ), a probiotic strain isolated from traditional fermented koumiss, exhibits health benefits such as anti-inflammatory and antioxidative effects, improvement of insulin resistance and mitigation of renal injury. However, whether LCZ can prevent peritoneal fibrosis remains unknown. Here, we assessed the effects of LCZ in a mouse model of PD-induced peritoneal fibrosis. Our results showed that the administration of LCZ significantly ameliorated peritoneal fibrosis in experimental mice. Macrophage infiltration, inflammatory M1 polarization and inflammatory cytokines in peritoneal dialysis effluents were effectively reduced by LCZ. Meanwhile, LCZ corrected gut dysbiosis and enriched beneficial bacteria that produce short-chain fatty acids, specifically Dubosiella, Lachnospiraceae, Parvibacter, and Butyricicoccus. Correspondingly, the local butyrate level in peritoneal dialysis effluents was significantly elevated by LCZ. Mechanistically, we found activation of PPARγ and inhibition of the NF-κB pathway in LCZ-treated mice, an observation that was replicated in a butyrate-treated macrophage cell line. In conclusion, our study suggests that LCZ is beneficial for preventing PD-induced peritoneal fibrosis through modulating the gut microbiota, enhancing butyrate production, activating PPARγ, and suppressing NF-κB-mediated inflammation.