Abstract: Hepatocellular carcinoma (HCC) often requires targeted therapy and immunotherapy due to frequent delayed diagnosis. Sorafenib, as the first targeted drug applied to HCC, has demonstrated a remarkable therapeutic effect in clinical treatment. However, its clinical implication has been limited by drug resistance and the insufficient understanding of the relevant mechanism. Wilms’ tumor 1-associated protein (WTAP), associated with tumor progression, remains unstated in sorafenib resistance. In this paper, WTAP expression patterns in HCC were systematically characterized through integrative analysis of The Cancer Genome Atlas (TCGA) datasets and spatial transcriptomic profiling. To delineate the potential mechanisms of WTAP-mediated sorafenib resistance in HCC, multimodal approaches integrating gene set enrichment analysis (GSEA), predictions from the “oncoPredict” package in vitro experiments, molecular docking simulations, and western blot validation were applied. To further investigate the role of WTAP in drug resistance, Hydrodynamic tail vein injection (HTVi) mouse models and immunohistochemistry were utilized. Significant WTAP upregulation was identified in HCC tissues, showing strong associations with tumor progression and adverse clinical outcomes. The knockdown of WTAP sensitized HCC cells to sorafenib in vitro. GSEA, molecular docking and western blot analysis demonstrated that WTAP induces the activation of extracellular signal-regulated kinase (ERK) signaling pathway, a critical link in chemoresistance mechanisms. In the HTVi HCC model, the combination of WTAP knockdown with sorafenib markedly suppressed tumor progression and boosted survival rates. These findings highlight that WTAP positively regulates the ERK pathway in HCC, promoting sorafenib resistance, therefore targeting WTAP may represent a novel strategy to potentiate sorafenib responsiveness in HCC.