Oxidative stress is associated with placental dysfunction and sub-optimal pregnancy outcomes. Therapeutic interventions to limit placental injury from oxidative stress are lacking. Punicalagin is an ellagitannin and a potent antioxidant in pomegranate juice. We showed that both pomegranate juice and punicalagin decrease oxidative stress and apoptosis in cultured syncytiotrophoblasts. p53 is involved in the oxidative stress-induced apoptosis in trophoblasts. We now test the hypothesis that punicalagin limits trophoblast injury in vitro by regulating the levels of p53. We examined the expression of p53, MDM2, p21, HIF1α and selected members of the BCL2 family of proteins in cultured syncytiotrophoblasts exposed to < 1% oxygen in the absence or presence of punicalagin. We found that punicalagin attenuated hypoxia induced apoptosis in syncytiotrophoblasts, as quantified by levels of cleaved PARP. This protective effect was in part mediated by reduced p53 activity shown by decreased expression of p21, lower HIF1α expression, and limited activity of caspases 9 and 3. There was no change in expression of proteins in the BCL2 family, which are also important in apoptosis. The data support a role for down regulation of p53 in the protection of human trophoblasts by punicalagin.