Highly invasive A431-III cells, which are derived from parental A431-P cells, were originally isolated by three successive passages through a Boyden chamber using a Matrigel-coated membrane support. The greater invasion potential shown by A431-III cells was due to their increased ability to spread/migrate, which was associated with enhanced MMP activity. The tumor progression events evoked by A431-P cells compared to A431-III cells may help identify useful strategies for evaluating the epithelial-mesenchymal transition (EMT) and these cell lines could be a reliable model for evaluating tumor metastasis events. Using this approach, we evaluated the effects of luteolin and quercetin using the A431-P/A431-III EMT model. These flavonoids reversed cadherin switching, downregulated EMT markers, and nullified the invasion ability of A431-III cells. Overexpression of MMP-9 resulted in induction of the EMT in A431-P cells and this could be reversed by treating with luteolin or quercetin. Cotreatment of A431-P and A431-III cells with epidermal growth factor (EGF) plus luteolin or quercetin resulted in a more epithelial-like morphology, led to reduced levels of EGF-induced markers of EMT, and caused the restoration of cell-cell junctions. E-cadherin was decreased by EGF, but increased by luteolin and quercetin. Our results suggest that luteolin and quercetin are potentially beneficial agents that target and prevent the occurrence of EMT in epidermal carcinoma cells. These chemicals also have the ability to attenuate tumor progression in A431-III cells. Luteolin and quercetin show inherent potential as chemopreventive/antineoplastic agents and do this by abating tumor progression through a reversal of EMT.