The tea flavonoid epicatechin gallate (ECG) exhibits a wide range of biological activities. In this study, the in vitro anticancer effects of ECG on SW480 colon cancer cell line was investigated by analyzing the cell cycle, apoptosis, key proteins involved in cellular survival/proliferation, namely AKT/phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinases (MAPKs), and the role of p53 in these processes. ECG induced cell cycle arrest at the G0/G1-S phase border associated with the stimulation of p21, p-p53, and p53 and the suppression of cyclins D1 and B1. Exposure of SW480 cells to ECG also led to apoptosis as determined by time-dependent changes in caspase-3 activity, MAPKs [extracellular regulated kinase (ERK), p38, and c-jun amino-terminal kinase (JNK)], p21 and p53 activation, and AKT inhibition. The presence of pifithrin, an inhibitor of p53 function, blocked ECG-induced apoptosis as was manifested by restored cell viability and caspase-3 activity to control values and reestablished the balance among Bcl-2 anti- and proapoptotic protein levels. Interestingly, ECG also inhibited p53 protein and RNA degradation, contributing to the stabilization of p53. In addition, JNK and p38 have been identified as necessary for ECG-induced apoptosis, upon activation by p53. The results suggest that the activation of the p53-p38/JNK cascade is required for ECG-induced cell death in SW480 cells.