Targeting tumor-associated blood vessels to increase immune infiltration may enhance treatment effectiveness, yet limited data exists regarding anti-angiogenesis effects on the tumor microenvironment. We hypothesized that dual targeting of angiogenesis with immune checkpoints will improve both intracranial and extracranial disease. We used subcutaneous and left ventricle melanoma models to evaluate anti-PD-1/anti-vascular endothelial growth factor (VEGF) and anti-PD-1/lenvatinib (pan-VEGF receptor inhibitor) combinations. Cytokine/chemokine profiling and flow cytometry were performed to assess signaling and immune infiltrating populations. An in vitro blood-brain barrier model was utilized to study intracranial treatment effects on endothelial integrity and leukocyte transmigration. Anti-PD-1 with either anti-VEGF or lenvatinib improved survival and decreased tumor growth in systemic melanoma murine models; treatment increased TH1 cytokine/chemokine signaling. Lenvatinib decreased tumor-associated macrophages but increased plasmacytoid dendritic cells early in treatment; this effect was not evident with anti-VEGF. Both lenvatinib and anti-VEGF resulted in decreased intratumoral blood vessels. Although anti-VEGF promoted endothelial stabilization in an in vitro blood-brain barrier model while lenvatinib did not, both regimens enabled leukocyte transmigration. Combined targeting of PD-1 and VEGF or its receptors promotes enhanced melanoma anti-tumor activity, yet their effects on the tumor microenvironment are quite different. These studies provide insights into dual anti-PD-1 and anti-angiogenesis combinations.