Integrin targeted therapies by natural bioactive compounds have attracted attention in the field of oncology and cancer treatment. This study evaluates the potential of phenolic extract from the medicinal herb Ecballium elaterium L. seed oil (PEO) to inhibit the adhesion and migration of the highly invasive human fibrosarcoma cell line HT1080. At safe concentrations (up to 40 mg mL −1), results show that PEO dosedependently inhibits adhesion and migration of HT1080 to fibronectin (IC 50 = 18 mg mL −1) and fibrinogen (IC 50 = 12.86 mg mL −1). These observations were associated with the reduction of cell motility and migration velocity as revealed in the Boyden chamber and random motility using two-dimensional assays, respectively. Additional experiments using integrin blocking antibodies showed that PEO at the highest safe concentration (40 mg mL −1) competitively inhibited the attachment of HT1080 cell to anti-avb3 (>98%), anti-a5b1 (>86%), and to a lesser extent anti-a2 (>50%) immobilized antibodies, suggesting that avb3 and a5b1 integrins were selectively targeted by PEO. Moreover, PEO specifically targeted these integrins in human microvascular endothelial cells (HMEC-1) and dose-dependently blocked the in vitro tubulogenesis. In the CAM model, PEO inhibited the VEGF-induced neoangiogenesis confirming its antiangiogenic effect. Collectively, these results indicate that PEO holds promise for the development of natural integrin-targeted therapies against fibrosarcoma.