Gastroesophageal reflux disease (GERD) is a chronic condition resulting from the reflux of gastric contents into the esophagus, leading to symptoms such as heartburn and regurgitation. While proton pump inhibitors (PPIs) and H2-receptor antagonists (H2RAs) are commonly used pharmacologic options, comparative data on their efficacy remains variable across populations. This double-blind randomized controlled trial aimed to assess the relative effectiveness of PPIs versus H2RAs in managing symptomatic GERD. A total of 180 patients diagnosed with GERD based on clinical symptoms and endoscopic findings were randomized into two groups: Group A received a standard dose of omeprazole 20 mg once daily, while Group B received ranitidine 150 mg twice daily, for 8 weeks. Primary endpoints included symptom resolution (heartburn and regurgitation) measured using a validated GERD questionnaire, while secondary endpoints included endoscopic mucosal healing and quality-of-life improvement. At 8 weeks, Group A showed significantly greater symptom relief (82.2% vs. 58.9%, p < 0.001), higher rates of mucosal healing (78.9% vs. 54.4%, p = 0.002), and improved quality-of-life scores (p = 0.004). These findings suggest superior efficacy of PPIs over H2RAs in managing GERD, supporting the continued use of PPIs as first-line therapy in moderate to severe cases.