Background and Aims Liver ischemia/reperfusion (I/R) injury is a common pathophysiological change often involved in liver transplantation and hepatectomy. Competing endogenous RNA (ceRNA) regulatory network can participate in the occurrence and development of many diseases. However, there are only a few reports on the function of ceRNA network in liver I/R injury. This study was conducted to construct a ceRNA network related to liver I/R damage via bioinformatics approaches, and meanwhile to screen potential therapeutic drugs based on the differentially expressed genes.Methods The mRNA and miRNA expression chip data of liver I/R damage were obtained from the GEO database. Gene differential expression analysis was performed using the limma package in the R language, and the scatter plots, volcano plots and heat maps were drawn using the ggplot2 package. The protein-protein interaction (PPI) network was constructed using String database and Cytoscape software. The GO/KEGG function enrichment analyses were performed on the differentially expressed mRNAs screened out using Metascape database. The transcription factors that may regulate these differentially expressed genes were analyzed through the transcriptional regulatory network database. The miRNA-differentially expressed gene network was constructed using miRTarBase database. A ceRNA network was constructed through starBase: ceRNA database. The natural medicines that have potential effects on the expressions of key differentially expressed gene were screened using the Comparative Toxicogenomics Database (CTD).Results Two liver I/R injury mRNA data sets (GSE10654 and GSE117066) and one liver I/R injury miRNA data set (GSE72315) were obtained from the GEO database. A total of 16 genes up-regulated in I/R group and down-regulated in ischemic postconditioning (IPO) group, and 7 genes down-regulated in I/R group and up-regulated in IPO group were screened out by analyzing the mRNA expression data set using limma package and Venn diagram. The results of GO/KEGG functional enrichment analyses showed that the differential genes were mainly involved in the positive regulation of cell death and the biological process of response to extracellular stimuli, and participated in the MAPK signaling pathway. Transcription regulatory network database analysis revealed that six transcription factors (Trp53, Cebpb, Crebbp, Fos, Nfkb1 and SP1) may be involved in the regulation of these differentially expressed genes., two miRNA-mRNA axes (mmu-miR-32-5p-Btg2 and mmu-miR-9-5p-Mt2) may play an important role in liver I/R injury were obtained through miRTarBase database analysis and combined with the differential expression of miRNAs after I/R injury in the GSE72315 data set. Through starBase: ceRNA database analysis, 9 ceRNA networks were finally obtained, namely, the XIST/MEG8/LINC00963/MALAT1-miR-32-5p-Btg2 axis, XIST/NEAT1-miR-132-3p-Btg2 axis and HSPA9P1/RALGAPA1P1/RPS26P39-miR-9-5p-Dusp6 axis. Seven botanicals (quercetin, resveratrol, genistein, couestrol, curcumin, capsaicin, and scopolamine) that could exert potential therapeutic effects by reducing the expressions of key genes were screened out in the CTD database.Conclusion The important ceRNA networks in the process of hepatic I/R injury and potential therapeutic drugs are screened through bioinformatics analysis, which provide an important basis for further research of the pathogenesis of liver I/R injury and its therapeutic drugs.