Lenvatinib resistance is a major obstacle in the treatment of hepatocellular carcinoma (HCC). Phthalates, widespread environmental plasticizers, may contribute to therapeutic resistance, yet their impact on HCC remains unclear. In this study, we integrated network toxicology, molecular docking, and transcriptomic analyses to explore the potential link between phthalates and lenvatinib resistance. By intersecting phthalate-related genes and lenvatinib resistance signatures, we identified 40 phthalates-related lenvatinib resistance genes (PLRGs). A risk model based on eight genes, including HPX, was constructed and validated for prognostic prediction. HPX was highlighted as a central gene that interacts strongly with diethyl, dimethyl, and dioctyl phthalates and is significantly downregulated in HCC tissues and resistant cell lines. Functional assays revealed that HPX suppresses HCC cell proliferation, migration, invasion, and lenvatinib resistance, and its overexpression enhances drug sensitivity. Mechanistically, phthalate exposure activated the MAPK signaling pathway, while HPX inhibited this activation, as confirmed through Western blot and in vivo mouse models. Our findings suggest that phthalate exposure contributes to lenvatinib resistance in HCC via the HPX-MAPK axis and that HPX may serve as both a prognostic biomarker and therapeutic target for overcoming resistance in HCC treatment.