Background and study aim: Gastroesophageal reflux disease (GERD) is a prevalent condition marked by acid regurgitation and/or heartburn due to the reflux of gastric contents. This study aimed to evaluate the efficacy of Vonoprazan (P-CABs) versus Dexlansoprazole (PPIs) in cases diagnosed with gastroesophageal reflux disease. Patients and Methods This study was a randomized controlled open-label trial, this study represents the first of its kind in internal medicine at Zagazig University Hospitals, spanning the period from October 2024 to February 2025.It included eighty cases diagnosed with gastroesophageal reflux disease following upper GI endoscopy. Cases have been categorized into two groups, forty patients in each. Group A received Vonoprazan twenty milligrams once daily, whereas Group B received Dexlansoprazole sixty milligrams once daily for a duration of eight weeks. Primary Outcome Measure (Symptom relief assessed by the GERD-Q score), Secondary Outcome Measure (Frequency scale of the symptoms of gastroesophageal reflux disease questionnaire (FSSG), and mucosal healing by upper GI endoscopic evaluation. Results Analysis revealed no statistically significant difference in GERD Q scores between groups A and B before treatment (mean ± SD: 15.92 ± 1.36 vs. 15.84 ± 1.61, p = 0.81). Following treatment, both groups exhibited significant improvement (99.42% in group A and 99.39% in group B), although this difference was not statistically significant (0.09 ± 0.23 vs. 0.10 ± 0.27, p = 0.65).