Hemangioma (HA) is one of the most common benign vascular tumors among children. Propranolol is used as the first-line treatment for hemangioma and is a non-selective blocker of the -adrenergic receptor. -elemene is a compound extracted from Rhizoma zedoariae and has been approved for the treatment of tumors in clinical practice. However, the combinatorial effects of -elemene and propranolol in the treatment of HA remains unclear. This study explored the combinative effects and mechanisms of -elemene and propranolol using hemangioma-derived endothelial cells (HemECs). Cytotoxic assays showed that the combinatorial treatment of -elemene and propranolol did not increase the cytotoxic effects of HemECs. Furthermore, functional analysis showed that the combinatorial treatment with -elemene and propranolol significantly inhibited the proliferation, migration, and tube formation of the HemECs compared to the single treatment regimens. Mechanistic analysis showed that combinative treatment with -elemene and propranolol synergistically down-regulated the hypoxia-inducible factor-1 alpha/vascular endothelial growth factor-A (HIF-1-/VEGFA) signaling pathway. Additionally, in a xenograft tumor model, angiogenesis in the combinatorial treatment group was significantly lower than in the control, propranolol, and -elemene treatment alone groups. Our results suggest that -elemene combined with propranolol can significantly inhibit the proliferation, migration, and tube formation of HemECs via synergistically down-regulating the HIF-1-/VEGFA signaling pathway without increasing any cytotoxic side effects.