Background: Depressive disorders are more common in patients with diabetes mellitus (DM) compared to the general population. Objectives: Due to heterogeneous evidence on the impact of antidepressants on serum glucose profile, this study was conducted to examine the effects of sertraline and fluoxetine on serum glucose levels in patients with comorbid depression and diabetes. Methods: In this randomized controlled trial, 40 adult patients with DM and depression were randomly allocated into two groups (n = 20 per group). The first group received 50 - 200 mg/day of sertraline, and the second group received 20 - 60 mg/day of fluoxetine. The Beck Depression Inventory (BDI-II) was used to determine depression severity, and body mass index (BMI), blood pressure, serum lipid profile, fasting blood sugar (FBS), 2-hour post-prandial blood glucose, and HbA1c were measured at the baseline and 12 weeks after the intervention. Results: Body mass index (P = 0.40), systolic blood pressure (P = 0.41), FBS (P = 0.46), 2-hour post-prandial blood glucose (P = 0.53), HbA1c (P = 0.59), serum total cholesterol (P = 0.78), and LDL cholesterol (P = 0.62) insignificantly reduced in both groups after the intervention compared to the baseline; however, the reduction in serum triglyceride level was statistically significant (P = 0.04). Also, the depression severity score was reduced in both groups; however, the difference was not statistically significant (P = 0.27). Conclusions: In adult patients diagnosed with comorbid depression and type II diabetes mellitus, three months of treatment with sertraline or fluoxetine comparably mitigated depressive symptoms and reduced HbA1c, FBS, and 2-hour post-prandial blood glucose.