Background: Cirrhosis is defined as diffuse liver fibrosis (LF) caused by various chronic liver diseases and characterized by excessive deposition of extracellular matrix in liver tissue. However, the molecular mechanism of cirrhosis has not been well understood. This study aimed to identify significant gene expression profiles that participate in cirrhosis pathogenesis using bioinformatics and to discover novel biomarkers. Methods: Two LF datasets (GSE14323 and GSE139602), both consisted of cirrhosis patients and healthy individuals, were obtained from the Gene Expression Omnibus (GEO) database and used for further analysis. Firstly, differential expression analyses were conducted to discover overlapping differentially expressed genes (DEGs) using the limma package. Next, the clusterProfiler function was adopted to carry out the Gene Ontology (GO) and Kyoto Encyclopedia of Genes as well as Genomes (KEGG) enrichment analyses. Furthermore, proteinprotein interaction (PPI) network of the DEGs was constructed in the STRING database. In addition, hub genes were extracted through the cytoHubba plug-in. To verify the results we observed from the bioinformatics analysis, mouse models were established by receiving Carbon tetrachloride (CCl4) injections or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Results: A total of 81 upregulated and 21 downregulated overlapping DEGs were identified in cirrhosis tissues compared to healthy controls. 9 hub genes included SPP1, SOX9, THBS2, LUM, LAMA2, PECAM1, VIM, COL1A2, and COL3A1 were identified by the PPI analysis from the 81 upregulated overlapping DEGs. RT-PCR of the fibrotic liver tissues from the mouse model showed that the mRNA levels of Spp1, Sox9, Col1a2 and Col3a1 were up-regulated in mice treated with CCl4, while Spp1, Thbs2, Lum, Pecam1, Vim, Col1a2, and Col3a1 were upregulated in mice treated with DDC. Predictive analyses provided drug compounds that are associated with LF. Conclusion: The present study identified hub genes that were associated with the occurrence of LF may provide reference for future studies to better explore the pathogenesis of cirrhosis, and play a possible role for developing drugs for LF.