Peucedanum praeruptorum Dunn (PP) root, traditionally used in Korea for respiratory disorders, has recently gained attention for its anticancer potential. This study examined the anti-angiogenic effects of its ethanolic extract (EPP) in endothelial cells and gefitinib-resistant lung cancer cells. In human umbilical vein endothelial cells (HUVECs), EPP markedly inhibited proliferation, migration, tube formation, and vascular permeability, suggesting its strong anti-angiogenic activity. Mechanistically, EPP suppressed VEGFR2 phosphorylation and downstream AKT/ERK signaling. Conditioned media from gefitinib-resistant PC9 (PC9/GR) cells enhanced angiogenesis in HUVECs compared to parental PC9 cells, reflecting the increased pro-angiogenic capacity of resistant cells. Notably, conditioned media from EPP-treated PC9/GR cells reduced these angiogenic responses, which correlated with selective downregulation of angiopoietin-1 (ANG-1). Supplementation with recombinant ANG-1 restored HUVEC migration, implicating ANG-1 suppression as a key mechanism. Moreover, praeruptorin A and B, major constituents of EPP, exerted comparable anti-angiogenic effects and were predicted to interact with the VEGFR2 kinase domain in docking analyses. Together, these findings indicate that EPP disrupts tumor angiogenesis through dual mechanisms: direct inhibition of VEGFR2 signaling in endothelial cells and suppression of tumor-derived ANG-1 in gefitinib-resistant lung cancer cells.