Depression is a complex and multifaceted disorder with poorly defined etiology and numerous risk factors. Despite the availability of several antidepressant classes, many treatments have limitations that compromise their effectiveness and impact patients’ quality of life. Depression and diabetes share pathophysiological mechanisms, such as insulin resistance, inflammation, and neuroplasticity. This review aims to explore the potential of oral antidiabetic therapy as an alternative or adjunct treatment for depression by examining pre-clinical studies to understand mechanisms of action and clinical studies to evaluate therapeutic efficacy. A bibliographic search was conducted in the PubMed database, and articles were selected using defined inclusion and exclusion criteria. The selected studies were categorized into two groups: pre-clinical studies and clinical studies. Detailed analysis was conducted for each study using a structured reading form. Key findings highlighted Metformin and Pioglitazone as the most studied drugs with promising effects. Pre-clinical studies showed that Metformin reduced depression-like behaviors in animal models, and when combined with conventional antidepressants, it enhanced their therapeutic effect. Similarly, Pioglitazone demonstrated significant antidepressant properties by alleviating depressive symptoms in clinical settings, particularly in patients with concurrent depression and diabetes. The mechanisms identified in these studies, including modulation of insulin resistance and improvements in neuroplasticity, provide insight into the efficacy of oral antidiabetic therapy for depression. These findings suggest a dual benefit for patients with comorbid diabetes and depression. While the evidence supports the potential role of these therapies, further research is required to optimize treatment protocols, investigate long-term outcomes, and expand the understanding of the underlying biological pathways.