Emotional stress, including depression, might result in increased gastroesophageal reflux disease symptoms. In this paper, we aim to evaluate the associations of depressive symptoms, depressive symptom severity, and symptom clusters with acid reflux medication use, considering the potential interaction effect of sex. Data from the 2007-2018 National Health and Nutrition Examination Survey were used. Participants older than 18 years were included if they responded to the depressive symptoms and prescription medication questionnaires. This study included 31,444 participants, of whom 2871 had depressive symptoms. Participants with depressive symptoms had significantly higher odds of using antacids (aOR = 1.735
p <
0.001), histamine-2 receptor antagonists (H2RAs) (aOR = 1.653
p <
0.001), and proton pump inhibitors (PPIs) (aOR = 1.723
p <
0.001). A positive association was also found between depressive symptom severity and use of antacids (aOR = 1.054
p <
0.001), H2RAs (aOR = 1.048
p <
0.001), and PPIs (aOR = 1.053
p <
0.001). Moreover, increases in cognitive-affective and somatic scores were associated with increased odds of using antacids (aOR = 1.080 for cognitive, 1.102 for somatic
p <
0.001), H2RAs (aOR = 1.078 for cognitive, 1.083 for somatic
p <
0.001), and PPIs (aOR = 1.075 for cognitive, 1.105 for somatic
p <
0.001). No significant sex interaction effects were observed. Adjusted models demonstrated no significant associations between depressive symptoms and the duration of medication use. This study provides evidence for the association between depressive symptoms and acid reflux medication use, highlighting the need to screen for related symptoms in patients with depressive symptoms.