Our study presents a novel humanized VEGFA model (B-hVEGFA mice) to investigate VEGFA-targeting therapies’ efficacy in limiting cancer cell growth and angiogenesis. After replacing the murine Vegfa gene with human VEGFA, we confirmed comparable expression levels in various organs. Tumor studies demonstrated significant inhibition of tumor growth with bevacizumab analog treatment in the humanized mice. Moreover, a triple humanized model expressing VEGFA, PD-1, and PD-L1 offers a platform to explore combination therapies targeting VEGFA and immune checkpoints for cancer treatment.