We investigated the effects of neuron-restrictive silencer factor (NRSF) on proliferation of endogenous nerve stem cells (NSCs) and on mu- and delta-opioid receptor (MOR/DOR) expression in rats after cerebral ischemia. Among 100 rats subjected to cerebral ischemia, 20 rats were transfected with NRSF shRNA, and the remaining 80 were randomly assigned to normal, sham, model, and negative control (NC) groups. On days 7, 14, and 28 after ischemia and reperfusion, neurological function scores were assigned and a step-down passive avoidance test was conducted. Nerve function scores, step-down reaction periods, error times and apoptosis rates, as well as levels of B-cell CLL/lymphoma 2 (Bcl-2), BCL2-associated X protein (Bax), and NRSF expression were lower in the NRSF shRNA group than in the model and NC groups. By contrast, step-down latency, numbers of bromodeoxyuridine-positive cells, MOR/DOR expression, and phosphorylation of extracellular signal regulated protein kinase (ERK) and cAMP response element binding protein (CREB) were higher in the NRSF shRNA group than in the model and NC groups. These results suggest that by up-regulating MOR/DOR expression, NRSF knockdown accelerates recovery of neurological function after cerebral ischemia, at least in part by promoting NSC proliferation and inhibiting apoptosis.