Vonoprazan is a novel potassium-competitive acid blocker (P-CAB) that works through a reversible potassium-specific competitive mechanism to inhibit active proton pumps directly. In contrast to standard proton pump inhibitors, vonoprazan does not require acid activation or any time constraints for its administration. As a result of its rapid onset and prolonged action, vonoprazan is a suitable option for PPI. In this study, we compare the efficacy of vonoprazan and PPIs in treating Gastroesophageal Reflux Disease (GERD), H. pylori, and post-endoscopic submucosal dissection (ESD) bleeding and ulcers. A PRISMA-guided systematic review was conducted on Pubmed. It included English or Portuguese articles published in the last five years describing adult patients treated with vonoprazan and/or PPI for GERD, H. pylori, or post-endoscopic dissection of the gastroesophageal submucosa bleeding and ulcers. There were six articles on GERD. Half suggested vonoprazan was superior to PPIs, while the other half considered it non-inferior or of comparable efficacy. There were 19 articles on H. pylori eradication, and vonoprazan outperformed PPI in 68,42% (13/19) of them. Vonoprazan was more effective than PPIs in 8 of the 13 studies chosen for post-ESD and ulcer prevention. As a result, in most studies, vonoprazan is either superior or not inferior to PPIs. However, the racial bias of the results is a significant limitation, as many of these studies were conducted in the Japanese population. More research on greater racial diversity is required. Nonetheless, in the current scenario, vonoprazan is a potential alternative pharmacological treatment for post-ESD bleeding and ulcers, GERD, and H. pylori.