Purpose <p>Hypoxia and mitochondrial dysfunctions are key contributors to the progression of liver hepatocellular carcinoma (LIHC). This study aimed to investigate the roles of hypoxia and mitochondrial energy metabolism-related differentially expressed genes (HMEMRDEGs) in the prognosis of LIHC.</p> Methods <p>HMEMRDEGs were identified from the LIHC cohort from the Cancer Genome Atlas (TCGA) dataset by intersecting DEGs from TCGA-LIHC with hypoxia-related genes (HRGs) and mitochondrial energy metabolism-related genes (MEMRGs). The prognostic impact of HMEMRDEGs was determined, and enrichment analyses were performed on essential genes. A HMEMRDEGs-based risk score system was established using LASSO and multivariable Cox regression analyses. High- and low-risk patient groups were subjected to gene set variation, immune infiltration, and immunophenoscore analyses. A nomogram was established by combining the clinical features of patients with LIHC using a risk model.</p> Results <p>Twenty-eight HMEMRDEGs were identified. A prognostic model based on five key HMEMRDEGs revealed distinct biological characteristics between high- and low-risk LIHC groups. Functional enrichment analyses showed that these genes were involved in glucose metabolism and cancer-related signaling pathways, including AMPK and PI3K/Akt/mTOR. GSVA and immune infiltration analyses demonstrated that the high-risk group was enriched in oncogenic pathways and exhibited a more immunosuppressive microenvironment. Additionally, the high-risk group had significantly lower immunophenoscores, suggesting reduced responsiveness to immunotherapy.</p> Conclusions <p>Our results demonstrate the profound impact of HMEMRDEGs on LIHC progression. We established a predictive risk model incorporating 5 key genes, which serves as a prognostic predictor in LIHC.</p>