Melatonin, as a dietary supplement, has a potent neuroprotective effect and exerts a certain antidepressant effect. This study explored the molecular mechanisms and targets of melatonin on chronic stress-induced hippocampal damage from the perspective of inhibiting inflammatory cytokines release. Our results indicated that melatonin alleviated chronic restraint stress (CRS)-induced inflammatory response and apoptosis, thus improving hippocampal structural damage and subsequent depression-like behaviors in rats. The radar map displayed that the change of TNF-α content was the most significant. Meanwhile, correlation analysis showed that TNF-α content was highly positively correlated with apoptosis. Molecular autodocking studies suggested that TNF-α converting enzyme ADAM17 as a potential target has a priority in docking with melatonin. Molecular mechanism studies indicated that melatonin inhibited CRS-induced activation of the ADAM17/TNF-α axis and its downstream proteins p38 and p53 phosphorylation in the hippocampus. Analogously, Both ADAM17 inhibitor TMI-1 and TNF-α inhibitor thalidomide relieved the effects of CRS on ADAM17/TNF-α axis and its downstream proteins phosphorylation, hippocampal apoptosis, hippocampal inflammatory response, and depression-like behaviors in rats. Altogether, these findings reveal that melatonin relieves CRS-induced inflammatory response and apoptosis, and subsequent depression-like behaviors by inhibiting ADAM17/TNF-α axis.