Angiogenesis contributes to the progression of several diseases including cancer or age-related macular degeneration and is crucially driven by pathologically hyperactive endothelial cells (ECs). Targeting angiogenic processes in ECs thus represents a promising strategy to treat these conditions. Vioprolide A (vioA) is a myxobacterial cyclic depsipeptide that targets the nucleolar protein 14 (NOP14) and possesses strong anti-cancer and anti-inflammatory actions. Here, we present evidence that vioA promotes anti-angiogenic actions in vivo and in ECs in vitro. VioA reduced the choroidal neovascularization after laser-induced photocoagulation in mice in vivo, the sprouting of choroidal explant cultures ex vivo and key angiogenic features of ECs in vitro. Mechanistically, vioA decreased VEGFR2 protein levels and phosphorylation leading to impaired downstream pro-angiogenic signaling. Concurrently, vioA influenced TAZ signaling by diminishing its nuclear translocation and protein level, resulting in a reduced expression of pro-angiogenic target genes and dynamic cytoskeletal remodeling. Surprisingly, vioA induced pro-survival signaling in ECs by activating Akt and inhibiting p53-dependent apoptosis. Knockdown of the cellular target NOP14 further revealed a partial involvement in the anti-angiogenic and pro-survival actions of vioA. Taken together, our study introduces vioA as an interesting anti-angiogenic compound that warrants further investigations in preclinical studies.