Background: Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal disorders that can disturb patients’ respiratory indices. Proton pump inhibitors (PPIs) such as omeprazole are currently the most common treatment in the patients. PPI-refractory GERD is a clinical problem constituting around 30% of patients with GERD. Objectives: The aim of this study was to investigate the effects of diaphragmatic breathing (DB) and omeprazole on respiratory indices (RI) and diaphragmatic excursion (DEX) in patients with GERD. Methods: This is a clinical trial conducted for eight weeks among 40 patients with severe GERD in Tehran in 2018. The block randomization method was designed to randomize 40 patients into two groups (DB and control) that resulted in equal sample sizes. The control group received omeprazole 20 mg once daily, and the DB group, in addition to omeprazole, performed DB. Respiratory indices, including (Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 second (FEV1), Peak Expiratory Flow (PEF)), and DEX were evaluated before, immediately, and six weeks after the end of intervention by spirometry and ultrasonography; respectively. Results: There was no significant difference in the RI and DEX before the intervention between groups. FVC (P = 0.04) and PEF (P = 0.02) significantly changed in the control group, but FEV1 (P = 0.001), FVC (P = 0.002), PEF (P = 0.001) and DEX (0.001) significantly changed after DB. There was a significant difference in terms of RI between before and followed up in DB. Conclusions: Diaphragmatic breathing with omeprazole had more effects on RI and DEX than omeprazole alone. The positive effects of DB remain at least six weeks after the end of the intervention.