Gastric ulcer is a common and global disease with high recurrence rate. It has been shown that selective serotonin-norepinephrine reuptake inhibitor duloxetine had protective effect on indomethacin-induced gastric ulcer, which was escorted by inflammation in the gastric mucosa. Cytokines, small-molecule peptides secreted from a variety of cells, are the principal mediators of inflammation. By screening the differential expression of cytokines in the gastric mucosa using cytokine array, we found that indomethacin induced increase in cytokines which promoted inflammation responses, whereas the protective effect of duloxetine was mediated through correcting the imbalance between pro-inflammatory cytokines and anti-inflammatory cytokines in gastric mucosa. Among them, RANTES was a key mediator in the prophylactic effect of duloxetine against indomethacin. We further identified that the protection was mediated by RANTES-chemokine receptor type 5 (CCR5) axis and inhibition of the axis by Met-Rantes or a CCR5 antagonist maraviroc suppressed the protection of duloxetine. Considering the pharmacologic action of duloxetine on reuptake of monoamine neurotransmitters, we examined the serotonin, norepinephrine and dopamine contents in the blood and discovered 20 mg/kg duloxetine increased serotonin levels in platelet-poor plasma, thus promoting expression of RANTES in gastric mucosa. Furthermore, increased RANTES activated PI3K-AKT-VEGF signaling pathway, which may be attributed to the protective effect of VEGF on endothelial cells and vessels in gastric mucosa. Together, our results identified the role of cytokines, particularly RANTES, and the underlying mechanisms in protection of duloxetine against indomethacin-induced gastric ulcer, which advanced our understanding in inflammatory modulation by monoamine-based antidepressant.