Introduction: Elaeagnus angustifolia (EA) is a medicinal plant that has been used for centuries in treating many human diseases, in the Middle East, including fever, amoebic dysentery, gastrointestinal problems. However, the effect of EA plant extract on human cancer progression especially oral malignancy has not been investigated yet. Thus, first we examined the effect of EA flower extract on angiogenesis in ovo, and on selected parameters in human oral cancer cells. Materials and methods: Chorioallantoic membranes (CAMs) of chicken embryos at 3-7 days of incubation were used to assess the effect EAflower plant extract on angiogenesis. Meanwhile, cell proliferation, soft agar, cell cycle, cell invasion and cell wounding assays were performed to explore the outcome of EA plant extract on FaDu and SCC25 oral cancer cell lines. On the other hand, western blot analysis was carried out to evaluate E-cadherin and Erk1/Erk2 expression and activation, respectively, in FaDu and SCC25 under the effect of EA extract. Results: Our data show that EA extract inhibits cell proliferation and colony formation, in addition to the initiation of Scell cycle arrest and reductionof G1/G2 phases. In parallel, EA extract provokes differentiation to an epithelial phenotype “mesenchymal-epithelial transition: MET” which is the opposite of “epithelial-mesenchymal transition, EMT”: an important event in cell invasion and metastasis. Thus, EA extract causes a dramatic decrease in cell motility and invasion abilities of FaDu and SCC25 cancer cells in comparison with their controls. These changes are accompanied by an up-regulation of E-cadherin expression. The molecular pathway analysis of the EA flower extract reveals that it can inhibit the phosphorylation of Erk1/Erk2, which could be behind the inhibition of angiogenesis, the initiation of MET event and the overexpression of E-cadherin. Conclusions: Our findings indicate that EA plant extract can downgrade human oral cancer progression by the inhibition of angiogenesis and cell invasion via Erk1/Erk2 signaling pathways.