Objective: Bipolar disorder and unipolar depressive disorder are complex phenotypes. There appear to be phenotypical, mechanistic, and therapeutic differences between bipolar depression (BD) and unipolar depression (UD). There is a need for understanding the underlying biological variation between these clinical entities. The role of oxidative processes underlying bipolar disorder and depression has been demonstrated. Thiol-disulfide homeostasis (TDH) is a recent oxidative stress marker. In this study, we aimed to inspect patients with bipolar depression and unipolar depression in terms of thiol-disulfide balance and to compare them with healthy controls. Methods: Patients admitted to the outpatient clinic of Ankara Numune Training and Research Hospital and diagnosed either as a depressive episode with bipolar disorder (n = 37) or unipolar depression (n = 24) according to DSM-5 criteria, along with healthy controls (HC) (n = 50), were included in the study. Native thiol, total thiol, and disulfide levels were compared across the groups. Results: In comparison to HC, both BD and UD groups had higher disulfide levels, disulfideative thiol ratio, and disulfide/total thiol ratio. No significant differences between BD and UD were detected in terms of disulfide level, disulfideative thiol ratio, and disulfide/total thiol ratio. Conclusion Increased levels of disulfide, native thiol, and disulfide/total thiol ratios compared to healthy controls in both UD and BD groups may be indicative of the presence of oxidative damage in these two clinical conditions. To clarify the role of oxidative stress in the pathophysiology of depressive disorders and investigate TDH, longitudinal studies in patients with medication-free UD and BD are required.