Hepatocellular carcinoma (HCC) is definitely an aggressive liver malignancy that’s hard to treat without any approved biomarker based targeted therapies. FGF19-FGFR4 signaling blockade continues to be lately recognized as an encouraging avenue to treat a subset of HCC patients. Using HCC relevant xenograft and PDX models, we reveal that Lenvatinib, an authorized multi-kinase inhibitor, strongly enhanced the effectiveness of FGFR4 inhibitor H3B-6527. This enhanced combination effect isn’t because of enhanced FGFR4 inhibition which is likely because of cell non-autonomous VEGFR activity of Lenvatinib. This cell non-autonomous mode of action was further based on strong in vivo combination effectiveness using the mouse specific VEGFR2 antibody, DC101, which cannot cell-autonomously hinder pathways in human xenografts. Mechanistic studies demonstrated the combination led to enhanced effectiveness through elevated anti-angiogenic and anti-tumorigenic activities. Overall, our results indicate this combination could be a impressive treatment choice for FGF19 driven HCC patients, and supply preclinical validation of the combination that may be readily tested within the clinical setting.