Degeneration of the dopaminergic neurons in the substantia nigra and the resultant dopamine depletion from the striatum are the hallmarks of Parkinson’s disease (PD) and are responsible for the disease’s cardinal motor symptoms. The transcriptional repressor Neuron-Restrictive Silencer Factor (NRSF), also known as RE1-Silencing Transcription Factor (REST), was originally identified as a negative regulator of neuron-specific genes in non-neuronal cells. Our previous study showed that mice deficient in neuronal NRSF/REST expression were more vulnerable to the noxious effects of the dopaminergic neurotoxin MPTP. Here, we found that brain-specific deletion of NRSF/REST led to more severe damages to the nigrostriatal pathway and long-lasting behavioral impairments in mice challenged with MPTP. Moreover, compared to wild-type controls, these mice showed increased neurogenesis shortly after MPTP exposure, but reduced neurogenesis later on. These results suggest that NRSF/REST acts as a negative modulator of neurogenesis and a pro-survival factor of neural stem cells under both normal conditions and during the course of PD.