Major depressive disorder (MDD) and diabetes mellitus (DM) remain among the most prevalent diseases and the most significant challenges faced by medicine in the 21st century. The frequent co-occurrence and bidirectional relationship between the two conditions necessitates the identification of treatment strategies that benefit both. The purpose of this study was to systematically review and meta-analyze data on the efficacy and safety of agomelatine (AGO) in the treatment of patients with depression with comorbid diabetes to explore its potential mechanism of action in both diseases and its impact on diabetic parameters. Following PRISMA guidelines, a total of 11 studies were identified, both preclinical and clinical trials. Agomelatine has shown great potential as a treatment option for patients with diabetes and comorbid depression and anxiety. In addition to improving depressive and anxiety symptoms, it is also beneficial in glycemic control. A meta-analysis demonstrated a statistically significant reduction in glycated hemoglobin (HbA1C) and fasting blood glucose (FBG) levels following AGO administration over a period of 8–16 weeks. The administration of agomelatine was found to result in a significantly greater reduction in HbA1C than that observed with the selective serotonin reuptake inhibitor (SSRI) medications (namely fluoxetine, sertraline, and paroxetine) during 12–16 weeks of therapy. Furthermore, AGO has been found to be at least as effective as SSRIs in reducing depressive symptoms and more effective than SSRIs in reducing anxiety symptoms. The safety of such treatment is similar to SSRIs; no severe adverse events were reported, and the incidence of some side effects, such as insomnia and sexual dysfunction, are even less often reported. Particularly promising is also its potential action in improving some diabetic complications reported in preclinical trials. This might be through mechanisms involving the reduction in oxidative stress, anti-inflammatory effects, and potentially noradrenergic or NMDA receptor modulation. Further clinical studies on larger sample sizes, as well as elucidating its mechanisms of action, especially in the context of diabetic complications, are needed. Research should also focus on identifying the patient subpopulations most likely to benefit from agomelatine treatment.