Objective To evaluate the protective effect of epigallocatechin-3-gallate (EGCG) on cisplatin (CIS)-induced acute kidney injury (AKI) in rats based on network pharmacology and in vivo animal model experiments. Methods Targets of EGCG and AKI were collected from the TCMSP, Gene Cards, and OMIM websites, and a protein-protein interaction network was constructed based on the intersection. The intersection targets were analyzed visually using Cytoscape 3. 9. 1 and the key targets were screened out. Kyoto Encyclopedia and of Genes and Genomes and Gene Ontology enrichment analyses were carried out using the DAVID database. Thirty-two male Wistar rats were divided randomly into four groups: CON group, EGCG group, CIS group, and CIS + EGCG group. Rats in the control and CIS groups were given normal saline every day, rats in the EGCG and CIS + EGCG groups were given EGCG (40 mg / kg) every day for 28 d, and rats in the CIS and CIS + EGCG groups received an intraperitoneal injection of CIS (7 mg / kg) on the 26th day. Blood and tissue samples were obtained on the 29th day. Serum urea nitrogen and creatinine levels were detected, renal pathology was observed by HE staining, and apoptosis in renal tissue was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling. Western Blot, qRT-PCR, and immunohistochemistry were used to verify the result. Results Eighty-seven genes intersecting EGCG and AKI and 25 core targets were screened from network pharmacology, which influenced the development of AKI via signal pathways such as PI3K/ Akt and various biological processes. EGCG pretreatment significantly reduced serum levels of serum urea nitrogen and creatinine, improved the renal pathology, and reduced renal tissue apoptosis in AKI rats. Western Blot, qRT-PCR and immunohistochemistry showed that pretreatment with EGCG activated the PI3K/ Akt pathway. Conclusions EGCG alleviates CIS-induced AKI in rats via the PI3K/ Akt signaling pathway.