Liver cancer is the sixth most frequently diagnosed primary malignancy and ranks as the third leading cause of cancer-related death worldwide in 2020. ER stress also plays a vital role in the pathogenesis of malignancies. In the current study, we aimed to construct an endoplasmic reticulum stress-related genes (ERGs) signature to predict the overall survival (OS) of patients with HCC. Differentially expressed ERGs (DE-ERGs) were analyzed using The Cancer Genome Atlas (TCGA-LIHC cohort) and International Cancer Genome Consortium (ICGC-LIRI-JP cohort) databases. The prognostic gene signature was identified by the univariate Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO)-penalized Cox proportional hazards regression analysis. The predictive ability of the model was evaluated by utilizing Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curves. Gene set variant analysis (GSVA) was performed to explore the underlying biological processes and signaling pathways. CIBERPORT and single-sample Gene Set Enrichment Analysis (ssGSEA) were implemented to estimate the immune status between the different risk groups. A total of 113 DE-ERGs were identified between 50 normal samples and 365 HCC samples in the TCGA-LIHC cohort, and 48 DE-ERGs were associated with OS through the univariate Cox regression. A six DE-ERGs (, , , , , ) signature was constructed and classified patients into high-risk and low-risk groups. The risk score was an independent prognostic indicator for OS (HR > 1, < 0.001). The function enrichment analysis indicated that cell cycle, RNA degradation, protein localization, and cell division were the main biological processes. The high-risk group had higher immune cell infiltration levels than those of the low-risk group. We predicted the response to targeted therapy in high- and low-risk patients with HCC and found that the high-risk patients were more sensitive to pazopanib. At last, we verified the expression of the six gene patterns in HCC tissues by qRT-PCR and immunohistochemistry. This signature may be a potential tool to provide a choice for prognosis prediction and personal management of patients with HCC.