Background: Stress-induced gastrointestinal bleeding (SIGB) frequently occurs in critically ill patients, posing significant clinical challenges. SIGB not only prolongs ICU stays but also escalates mortality rates and healthcare costs. Gastric acidity has been identified as a pivotal risk factor for SIGB. Consequently, acid-suppressing agents, such as proton pump inhibitors (PPIs) and histamine-2-receptor blockers (H2Bs), have become standard prophylactic treatments. Objectives: This comprehensive review article aims to explore the effectiveness of PPIs, H2B as for stress ulcer prophylaxis and determine the benefits and the risks of stress ulcer prophylaxis among critically ill patients. Conclusions: PPIs and H2Bs continue to be recognized as effective agents, their selection should be guided by individual patient risk factors. The evolving landscape of ICU support therapies, coupled with the potential adverse effects of acid-suppressive drugs, necessitates a nuanced approach in clinical decision-making.