Abstract: Objective Post-stroke depression was a serious threat to patient safety, which not only increased stroke symptoms, but also increased the patients' mental anguish. In order to reduce the patient's depressive symptoms, and to enhance the effect of prognosis to discover better drug treatment is very important. Thus, the effect of escitalopram and sertraline on inflammatory factors, NSE and NPY was investigated in patients with post-stroke depression in this study. Methods A total of 98 patients with post-stroke depression were divided into control group (49 cases) and observation group (49 cases). The patients in 2 groups received the conventional therapy, and patients in control group were additionally given sertraline therapy, and patients in observation group were additionally given escitalopram therapy. The treatment time was 8 weeks in 2 groups. To observe clinical effect, and effect of treatment on inflammatory factors (TNF-α and IL-6), NSE and NPY were compared before and after treatment in 2 groups. Results Total effective rate of observation group was 89. 80%, total effective rate of control group was 79. 59%, and there was no significant difference between observation group and control group (P > 0. 05). Compared with those before treatment, the levels of TNF-α and IL-6 decreased significantly at 8 weeks after treatment in 2 groups (P < 0. 05), and the levels of TNF-α and IL-6 of observation group decreased more significantly than those in control group (P < 0. 05). Compared with that before treatment, the level of NSE decreased significantly at 8 weeks after treatment in 2 groups (P < 0. 05), the level of NPY increased significantly at 8 weeks after treatment in 2 groups (P < 0. 05), and the changes of NSE and NPY of observation group were significantly more than those in control group (P < 0. 05). Incidence of adverse reactions of observation group was 24. 49%, incidence of adverse reactions of control group was 32. 65%, and incidence of adverse reactions had no significant difference in two groups (P > 0. 05). Conclusion Treatment with escitalopram and sertraline has reliable efficacy with mild adverse reactions, but escitalopram has better effect on IL-6, TNF-α, NSE and NPY in patients with post-stroke depression.