Selective estrogen receptor modulators (SERMs) such as bazedoxifene and raloxifene are recognized to mainly act via estrogen receptors (ERs), but there is no study examining the involvement of PPAR-gamma in their actions, especially in neurons undergoing hypoxia. Little is also known about age-dependent actions of the SERMs on neuronal tissue challenged with hypoxia. In this study, bazedoxifene and raloxifene protected neocortical cells against hypoxia at early and later developmental stages. Both SERMs evoked caspase-3-independent neuroprotection and increased protein levels of ERalpha (66 and 46 kDa isoforms) and PPAR-gamma. In addition, bazedoxifene enhanced expression of ERalpha-regulated Cyp19a1 mRNA. Using double siRNA silencing, for the first time we demonstrated a key role of ERalpha and PPAR-gamma in the neuroprotective action of the SERMs in neocortical neurons undergoing hypoxia. This study provides prospects for the development of a new therapeutic strategies against hypoxic brain injury that selectively target ERalpha and/or PPAR-gamma.