Saffron (Crocus sativus L.), a traditional food coloring and flavoring ingredient, has shown potential antidepressant activity in several preclinical and clinical studies. This study investigated the antidepressant effect and underlying mechanism of saffron extract (SE) using a chronic unpredictable mild stress (CUMS)-induced depressive mouse model. Mice subjected to 8-week CUMS were orally administered with SE or positive medicine fluoxetine for 6 weeks. Behavioral tests, histopathological analysis, proinflammatory cytokine levels, and protein/mRNA expression were evaluated to characterize the antidepressant effects of SE. Results showed SE improved depression-like behaviors, ameliorated hippocampal and neuronal damage, remitted neuroinflammation, and restored neuroplasticity in mice. The antineuroinflammatory effect of SE may be attributed to inhibition of microglial activation, NF-kappa B signaling pathway, and proinflammatory cytokines' secretion. In addition, the upregulation of hippocampal Creb, Bdnf, and Trkb, and related proteins by SE treatment may be a mechanism for neuroplasticity recovery. These results demonstrated the antidepressant effects of SE in a CUMS-induced depressive model and manifested the potential of saffron as a functional food for relieving depression.