Objective To construct and validate a prognostic model for sorafenib sensitivity-related genes in hepatocellular carcinoma (HCC) based on bioinformatics methods, and to explore the predictive ability of the model for prognosis and the efficacy for sorafenib treatment in HCC. Methods Differential gene analysis was performed on GSE109211 data set of Gene Expression Omnibus, LIHC cohort of The Cancer Genome Atlas (TCGA) and LIRI cohort of International Cancer Genome Consortium (ICGC). Sorafenib sensitivity-related genes in HCC were screened by intersection, and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway enrichment analysis was performed. A prognostic model was constructed using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression, and the patients were divided into high-risk and low-risk groups based on the median risk score. Survival analysis was conducted using Kaplan-Meier method and multivariate Cox regression analysis. The half inhibitory concentration (IC₅₀) of sorafenib was analyzed through the Genomics of Drug Sensitivity in Cancer (GDSC) and its relationship with risk score was explored. Results A total of 365 sorafenib sensitivity-related genes in HCC were screened, and the KEGG enrichment analysis revealed the presence of pathways associated with drug metabolism. Univariate Cox analysis identified 221 genes associated with prognosis, and a prognostic model containing 7 key genes (chaperonin containing TCP1 subunit 3［CCT3］, erythropoietin［EPO］, formimidoyltransferase cyclodeaminase［FTCD］, glucose-6-phosphate dehydrogenase［G6PD］, kinesin family member 20A［KIF20A］, phosphatidylinositol glycan anchor biosynthesis class U［PIGU］, and secreted phosphoprotein 1 ［SPP1］) was constructed by LASSO regression. Risk score＝CCT3×0.032＋EPO×0.055＋FTCD×(－0.026）＋G6PD×0.083＋KIF20A×0.039＋PIGU×0.144＋SPP1×0.009. The results showed that the high-risk group had a shorter survival time compared to the low-risk group (P＜0.001). Multivariate Cox analysis demonstrated that risk score was an independent prognostic factor. The IC₅₀ of sorafenib in the high-risk group was lower than that in the low-risk group, suggesting that the high-risk group may be more sensitive to sorafenib. Conclusion The constructed prognostic model for HCC based on sorafenib sensitivity-related genes has good prognostic value for HCC.