The peroxisome proliferator activated receptor coactivator 1 alpha (PGC-1alpha) is a nuclear transcriptional coactivator that is widely expressed in the brain areas. Over-expression of PGC-1alpha can protect neuronal cells from oxidant-induced injury. The purpose of the current study is to investigate the role of PGC-1alpha in the oxygen (anoxia) deprivation (OGD) neurons. The PGC-1alpha mRNA and protein level between control and OGD neurons were examined by real-time PCR and Western blot. More PGC-1alpha expression was found in the OGD neurons compared with the normal group. Over-expression of PGC-1alpha suppressed cell apoptosis while inhibition of the PGC-1alpha expression induced cell apoptosis in OGD neurons. Furthermore, increase of PGC-1alpha resulted in activation of N-methyl-D-aspartate (NMDA) receptor, p38, and ERK mitogen-activated protein kinase (MAPK) pathway. The blocking of the NMDA receptor by its antagonists MK-801 reduced PGC-1alpha mRNA expression in OGD neurons, while NMDA itself can directly induce the expression of PGC-1alpha in neuronal cells. At the same time, PD98059 (ERK MAPK inhibitor) and SB203580 (P38 MAPK inhibitor) also prevented the up-regulation of PGC-1alpha in OGD neurons and MK801 can inhibit the expression of P38 and ERK MAPK. These data suggested that the expression of PGC-1alpha was up-regulated in OGD mice cortical neurons, which protected the neurons against OGD injury. Moreover, this effect was correlated to the NMDA receptor and the ERK and P38 MAPK pathway. The protective effect of PGC-1alpha on OGD cortical neurons may be useful for stroke therapy.