Chronic kidney disease (CKD) is anticipated to be the fifth cause of global death by 2040 due to the lack of therapeutic tools currently. Lactobacillus paracasei (L. paracasei) isolated from artisanal fermented beverages has been implicated to have health-promoting properties. This study was designed to investigate the effects of L. paracasei on the mechanisms underlying renal injury regulation during CKD. A mouse CKD model was developed by 5/6 nephrectomy, and a fibrotic cell model was induced on human kidney-2 (HK-2) cells using TGF-β1. L. paracasei alleviated renal injury in CKD mice and TGF-β1-induced inflammatory and fibrotic injury in HK-2 cells. L. paracasei exerted in vitro and in vivo benefits by inducing lysine-specific demethylase 3A (KDM3A), and the knockdown of KDM3A markedly attenuated the therapeutic benefit of L. paracasei. KDM3A activated vacuole membrane protein 1 (VMP1) by removing the H3K9me1/2 modification on its promoter. L. paracasei activated autophagy to mitigate renal damage, which was compromised by the autophagy inhibitor 3-MA, allowing renal damage to intensify. Taken together, L. paracasei activates KDM3A expression and further activates VMP1 expression by removing inhibitory H3K9me1/2 modification on the VMP1 promoter to alleviate CKD by activating autophagy in renal tubular epithelial cells.