Background <p>The habenula (Hb) is a vital hub for the monoaminergic pathway and plays a crucial role in depression pathophysiology. However, owing to its small size and heterogeneity between individuals, there is no consensus on imaging alterations in the Hb in depression. This study aimed to examine the differences in the Hb between healthy controls (HCs) and patients with first-episode depression (FED) who were not taking any antidepressants, and to assess the value of Hb voxel cluster radiomic features in discriminating patients with FED from HCs.</p> Methods <p>This cross-sectional study included 94 participants (47 HCs and 47 patients with FED) who underwent 3-T magnetic resonance imaging. Differences in the Hb volume and T1 values between the two groups were examined. Correlations among volume, T1 value, depression severity, and age were also examined. Furthermore, a clustering-based radiomics model to differentiate patients with FED from HCs was developed and validated.</p> Results <p>In HCs, the Hb T1 value was positively related to age, whereas that of patients with FED showed no significant correlation. The prediction performance was improved in the clustering-based radiomics model (area under the curve [AUC] = 0.844) compared with the traditional model (AUC = 0.708).</p> Conclusions <p>Our findings imply that the Hb and its internal heterogeneity are imaging markers for depression studies.</p> Trial registration <p>Not applicable.</p>