Given the frequent concomitance between depression and gastroesophageal reflux disease (GERD), it is important to evaluate the change of depression in patients with GERD, especially considering the presence of esophageal mucosal breaks (MB). This study aimed to examine the change in the levels of depression in patients with GERD during proton-pump inhibitors (PPI) therapy. We designed a prospective cohort study to explore the profile of the alteration in depression with respect to the impact of esophageal MB. This study recruited 172 eligible patients with GERD between February 2016 and May 2018. The change in depression was defined as the difference between the respective Taiwanese Depression Questionnaire (TDQ) scores obtained at baseline and after PPI therapy. Multivariate linear regression models were used to estimate the factors associated with the change in depression. The results revealed statistically significant improvements in the TDQ score (mean score: baseline = 13.2, after PPI therapy = 10.9, p < 0.01, Cohen's d = 0.30) during PPI therapy for GERD. Moreover, the MB was an independent variable associated with changes in the TDQ score [B = 3.31, 95% confidence interval (CI): (1.12, 5.51), p < 0.01] and the improvement in depression [odds ratio = 0.38, 95% CI: (0.17, 0.86), p = 0.02]. Our findings revealed that depressive symptoms improved slightly following PPI therapy. Moreover, MB was an unfavorable prognostic factor for the improvement in depression.