Objective To observe the efficacy and safety of sertraline and celecoxib in the treatment of post-stroke depression（ PSD）. Methods From May 2015 to Decemer 2017， a total of 60 patients with PSD in the Neurology Department of the Third Affiliated Hospital of Xinxiang Medical University were randomly divided into study group（ n=30） and control group（ n=30）. Both groups were given conventional medication. The study group was additionally given sertraline and celecoxib， while the control group was given additionally sertraline and placebo for 6 weeks. The efficacy and safety of the two groups were evaluated with the Hamilton Depression table（HAMD） and adverse symptoms scale before treatment and at the 1st， 2nd， 4th， and 6th week after treatment. Results After 6 weeks of treatment， the effective rates of the study group and the control group were 83.3%（ 25/30） and 76.67%（ 23/30） respectively. There was significant statistical difference between the two groups（ χ2=6.75， P＜0.05）. The HAMD score of the study group at the 1st， 2nd， 4th and 6th week after treatment were all lower than those of the control group， and the differences were statistically significant（ P＜0.05）. There was no statistical significance in the difference of incidence of adverse effect［ 23.33%（ 7/30） vs 20.00%（ 6/30）］. In addition， the adverse effects were mild. Conclusions The efficacy of sertraline combined with celecoxib in the treatment of PSD was better than that of sertraline alone. It takes effect more quickly than sertraline alone. But the safety of sertraline combined with celecoxib in the treatment of PSD was comparable to that of sertraline alone.