Objective: To compare the effects of agomelatine and sertraline hydrochloride on the clinical efficacy, neurocytokine and monoamine transmitter metabolism in patients with post-stroke depression. Methods: A total of 94 patients with post-stroke depression admitted to our hospital from July 2015 to September 2018 were randomly divided into a test group and a control group with 47 cases each. The experimental group was treated with agomelatine 25 mg/d orally, which was increased to 50 mg/d after 1 week, and the control group was treated with sertraline hydrochloride 50 mg/d. The two groups were treated continuously for 8 weeks. The clinical efficacy, the incidence of adverse reactions and the Hamilton Depression Scale (HAMD) before and after treatment, the National Institutes of Health Stroke Scale (NIHSS) score, BI index, and neurocytokines were compared between the two groups. Derived Neurotrophic Factor: BDNF; Nerve Growth Factor: NGF), Monoamine Transmitter Metabolism (5-Hydroxytryptamine: 5-HT; 5-Hydroxyindoleacetic acid: 5-HIAA; Norepinephrine: NE) changes. Results: After treatment, the total effective rates of the experimental group and the control group were 82.97% (39 cases/47 cases) and 80.85% (38 cases and 47 cases), respectively, and the difference was not statistically significant (P>0.05). After treatment, there was no statistical difference between the test group and the control group in HAMD score, NIHSS score, and BI index (P>0.05). After treatment, there was no statistically significant difference between the test group and the control group in BDNF, NGF, 5-HT, 5-HIAA and NE (P>0.05). The incidence of adverse reactions in the experimental group and the control group were 17.02% and 19.14%, respectively, and the difference was not statistically significant (P>0.05). Conclusion: Agomelatine and sertraline hydrochloride have the same clinical efficacy in the treatment of post-stroke depression, and the adverse reactions are relatively mild.