AbstractTo explore the pharmacological mechanism of naringin (NRG) in renal fibrosis (RF) based on network pharmacology combined with molecular docking and experimental validation. We used databases to screen for the targets of NRG and RF. The “drug-disease network” was established using Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of targets were performed using Metascape, and molecular docking was performed using Schrödinger. We established an RF model in both mice and cells to validate the results of network pharmacology. After screening the database, we identified 222 common targets of NRG and RF and established a target network. Molecular docking showed that the target AKT had a good interaction with NRG. We found that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway was enriched by multiple targets and served as a target for experimental validation through GO and KEGG. The results revealed that NRG ameliorated renal dysfunction, reduced the release of inflammatory cytokines, decreased the expression of α-SMA, collagen I, and Fn, and recovered the expression of E-cad by inhibiting the PI3K/AKT signaling pathway. Our study used pharmacological analysis to predict the targets and mechanisms of NRG against RF. Furthermore, experiments proved that NRG inhibited RF effectively by targeting the PI3K/AKT signaling pathway.