Restraint stress indicated induction of morphology, biochemistry, and behavioral impairments. Several investigations have reported that curcumin has a protective effect against stress disturbance. The present study is designed to investigate the effects of curcumin on learning and memory, activity, biochemical, morphology changes, and apoptosis in the hippocampus and prefrontal cortex of restraint stress rats. For chronic restraint stress, the rats were kept in the restrainers for 2.5 h per day for 21 consecutive days. The animals received the gavage of curcumin every other day for 21 days. After stress, the animals were subjected to behavioral tests. In restraint stress rats, locomotor activity and step-through latency were decreased using open field and shuttle box, respectively. Then, the rats were sacrificed to assess their serum and brains. A reduction was seen in the serum malonedialdehyde levels and number of neurons in the hippocampus and prefrontal cortex. The significantly decreased serum total antioxidant capacity levels and increased apoptotic cells were observed in the hippocampus and prefrontal cortex. Finally, curcumin inhibited and reversed the changes of stress induced in the prefrontal cortex and hippocampus of the rats. These findings provided evidence for the protective effect of curcumin therapy on biochemical, morphology, and behavioral changes induced by restraint stress.