Angiogenesis and vasculogenic mimicry (VM) are crucial for the growth and metastasis of non-small-cell lung cancer (NSCLC). Most tumor angiogenesis inhibitors mainly target endothelial cell-mediated angiogenesis, ignoring tumor-cell-mediated VM and frequently leading to tumor recurrence and metastasis. Thus, development of bioactive molecules interfering with both tumor angiogenesis and VM is necessary. Identifying novel angiogenesis inhibitors from natural products is a promising strategy. Scoparasin B, a pimarane diterpene extracted from a marine-derived fungus, Eutypella sp. F0219, has an antibacterial effect. However, its effect on angiogenesis and VM remains unexplored. In this study, we first certified that scoparasin B showed a strong inhibition effect on angiogenesis and the VM process in vitro and ex vivo. Moreover, scoparasin B prominently impeded tumor growth, angiogenesis, and VM in an NCI-H1299 xenograft model. Further study revealed that scoparasin B restrained tumor angiogenesis and VM by reducing the VEGF-A level and suppressing the VEGF-A/VEGFR2 signaling pathway. This study first demonstrated scoparasin B inhibited tumor angiogenesis, VM, and tumor growth of NSCLC and revealed its underlying mechanism. These new findings further support the potential of scoparasin B as a novel angiogenesis inhibitor and give a hint for further exploring potential angiogenesis inhibitors from natural products.