BACKGROUND: Patients with functional dyspepsia (FD) are often accompanied by mood disorders (MDs). This study aimed to identify factors associated with MDs in patients with FD and evaluate the efficacy of targeted treatment plans. METHODS: Relevant scales were used to assess MDs. Patients with FD having MDs and acid reflux were treated with flupentixol and melitracen (FM) and acid-suppressive therapy (AST) (histamine-2 receptor antagonists (H2RAs) (group A) or proton pump inhibitors (PPIs) (group B)), and those without acid reflux (group C) did not receive AST. Patients with FD without MDs were randomly administered H2RAs (group D) or PPIs (group E). The primary endpoints were factors associated with MDs and improvement in gastrointestinal (GI) symptoms and MDs in patients with FD. RESULTS: A total of 362 patients with FD were enrolled in this study. Patients with FD having high GI score and low education were found prone to MDs. At week 2, the remission rate of overall GI symptoms and depression was significantly higher in group B than that in groups A and C [GI: 72.72% (32/44) vs. 47.73% (21/44) and 72.72% (32/44) vs. 38.94% (44/113), all < 0.05; depression: 72.22% (26/36) vs. 41.67% (15/36) and 72.22% (26/36) vs. 41.57% (37/89), all < 0.05]. Furthermore, the remission rate of overall GI symptoms was significantly higher in group E than that in group D [60.29% (41/68) vs. 42.65% (29/68), < 0.05]. At week 8, similar efficacies and adverse reactions were observed in these groups. CONCLUSION: The risk factors for MDs were high GI scores and low literacy rates. Thus, targeted treatment (FM+PPIs for patients with MDs; PPIs for patients without MDs) can improve the efficacy of patients with FD. CLINICAL TRIAL REGISTRATION: www.chictr.org.cn, identifier ChiCTR2100053126.