Background: Depression is one of the most common psychiatric disorders in diabetic patients, the occurrence of which affects the course of treatment and worsens its prognosis. Recently, accumulating evidence reveals a positive effect of saffron on relieving depressive symptoms. The aim of this study was to evaluate the efficacy of adding saffron to fluoxetine in the treatment of mild to moderate depression in type 2 diabetes mellitus (T2DM) patients. Methods: This randomized double-blinded study was conducted on patients with DMT2 with a diagnosis of mild to moderate depression (diagnosed using DSM-5 criteria) referring to Imam Khomeini hospital, Ahvaz, in 2021. A total of 60 patients were randomly assigned to receiving 30 mg/day saffron or placebo tablets along with fluoxetine (20 mg/day) for four weeks. The severity of depression was assessed based on the Hamilton Rating Scale for Depression (HRSD) score before and after the intervention, and incidence of treatment-related complications was investigated. Results: After the intervention, HRSD scores were reduced significantly in the both groups (P<0.0001); however, the reduction of depression symptoms in the saffron group was significantly higher in the intervention than in the placebo group (P=0.001). At the end of the intervention, all patients in the saffron group (100%) compared to 23 patients in the placebo group (76.7%) had an HDRS score ≤ 7 (P=0.011). No significant difference was detected in the incidence of adverse effects between the two groups (P=0.390). Conclusion: Our study’s results indicated the beneficial effects of the combination of saffron and fluoxetine on mild to moderate depression in DMT2 patients. Therefore, saffron could be considered as an effective and safe alternative to synthetic antidepressants for treating mild to moderate depression.