Hepatitis B virus (HBV) infection is a major cause of acute liver failure (ALF) in China, and mortality rates are high among patients who do not receive a matched liver transplant. This study aimed to determine potential mechanisms involved in HBV-ALF pathogenesis. Gene expression profiles under access numbers GSE38941 and GSE14668 were downloaded from the Gene Expression Omnibus database, including cohorts of HBV-ALF liver tissue and normal samples. Differentially expressed genes (DEGs) with false discovery rates (FDR) <0.05 and |log₂(fold change)| >1 as thresholds were screened using the Limma package. Gene modules associated with stable disease were mined using weighed gene co-expression network analysis (WGCNA). A co-expression network was constructed and DEGs were analyzed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A gene-based network was constructed to explore major factors associated with disease progression. We identified 2238 overlapping DEGs as crucial gene cohorts in ALF development. Based on a WGCNA algorithm, 10 modules (modules 1-10) were obtained that ranged from 75 to 1078 genes per module. Cyclin-dependent kinase 1 (CDK1), cyclin B1 (CCNB1), and cell-division cycle protein 20 (CDC20) hub genes were screened using the co-expression network. Furthermore, 17 GO terms and 6 KEGG pathways were identified, such as cell division, immune response process, and antigen processing and presentation. Two overlapping signaling pathways that are crucial factors in HBV-ALF were screened using the Comprehensive Toxicogenomics Database (CTD). Several candidate genes including HLA-E, B2M, HLA-DPA1, and SYK were associated with HBV-ALF progression. Natural killer cell-mediated cytotoxicity and antigen presentation contributed to the progression of HBV-ALF. The HLA-E, B2M, HLA-DPA1, and SYK genes play critical roles in the pathogenesis and development of HBV-ALF.