In the present study, we first investigated the neuroprotective effects of fluoxetine treatment in the chronic unpredictable mild stress (CUMS)-induced depression, and found that fluoxetine could significantly suppress neuroinflammation and apoptosis and ameliorated the depression-like behaviors in rats through p38 mitogen-activated protein kinase (MAPK) pathway within the dentate gyrus (DG) of hippocampus. This evidence concerns the gene MAPK14 and depressive symptom measurement.