<p>The hippocampus plays a crucial role in memory formation and emotional regulation, and is closely related to the pathology of depression. Escitalopram, a selective serotonin reuptake inhibitor, promotes neurogenesis in the dentate gyrus of the hippocampus and alters its structure. This study examined the relationship between these escitalopram-induced structural changes and treatment response in 107 patients with moderate to severe depression, of whom 56 were female (52.3%), with a mean age of 41.5 years (range: 25–73 years). Follow-up data were available for 71 patients (66.4%). Changes in the volume and laterality of hippocampal subregions were compared before and after escitalopram treatment between Responders to escitalopram (<i>n</i> = 53) and Nonresponders (<i>n</i> = 54). The results indicated that Responders had a larger left hippocampal volume (β = 189.3, 95% CI [71.4, 307.2], Cohen’s f² ≈ 0.094) and greater leftward laterality (β = 0.012, 95% CI [2.2 × 10⁻⁴, 0.024], Cohen’s f² ≈ 0.04) than Nonresponders at baseline. Additionally, the right hippocampus and right hippocampal head exhibited increased volume (β = 80.6, 95% CI [28.5, 132.8], Cohen’s f² ≈ 0.005; β = 50.4, 95% CI [22.2, 78.5], Cohen’s f² ≈ 0.006) and altered laterality (β = −0.011, 95% CI [−0.022, −4.1 × 10⁻⁴], Cohen’s f² ≈ 0.003; β = −3.3 × 10⁻⁴, 95% CI [−5.7 × 10⁻⁴, −8.3 × 10⁻⁵], Cohen’s f² ≈ 0.006) in response to escitalopram in Responders compared to Nonresponders. Furthermore, the volume changes in the right hippocampus and right hippocampal head correlated with core depressive symptoms. It is suggested that these volume changes play an important role in the improvement of core symptoms of depression by escitalopram treatment. These findings can help to reveal the mechanisms of action of selective serotonin reuptake inhibitors and have the potential to facilitate the early identification of patients who will respond to treatment.</p>