Hepatitis B virus-related acute liver failure (HBV-ALF) is characterized by a high fatality rate, its pathogenesis remains unclear and the therapeutic efficacy is limited. Ferroptosis which closely related to autophagy may be an underlying mechanism of HBV-ALF. The aim of this study was to identify key ferroptosis- and autophagy-related genes and pathways and provide insight into potential therapeutic approaches for HBV-ALF. We accessed the GSE14668 and GSE96851 datasets from the Gene Expression Omnibus (GEO) database and focused on differentially expressed genes (DEGs), ferroptosis-related DEGs (FRGs) and autophagy-related DEGs (ARGs). Hub genes were subsequently analyzed for enrichment, protein‒protein interactions (PPIs), and different immunological microenvironments, and potential hub gene were identified using MCC method and LASSO. Gene-targeted drugs were from the DGIdb and DrugBank databases.A total of 1462 DEGs were identified (726 upregulated and 736 downregulated). Enriched pathways included amino acid metabolism and immune and inflammatory responses, potentially serving as biomarkers for ALF pathogenesis. After integration with the FerrDb and HADb databases, 55 FRGs and 45 ARGs were identified. Thirteen hub genes (SLC7A11, HMOX1, G6PD, RRM2, KIF20A, HELLS, GPT2, GLS2, SPP1, CCR2, DCN, IRS1, and IGF1) were identified which closely associated with the immune microenvironment. Interplay among these genes occurred primarily through HMOX1. Moreover, we identified several hub gene-targeted drugs that may be effective in HBV-ALF treatment, such as riluzole, acetylcysteine, NADH and Vitamin E.Thirteen hub genes may play crucial roles in HBV-ALF progression, particularly, the HMOX1. Furthermore, drug target exploration offered promising avenues for therapeutic intervention in patients with HBV-ALF.