Acute appendicitis is among the most common causes of acute abdominal pain requiring emergency surgical intervention worldwide. Despite advances in diagnostic imaging and surgical techniques, infection control remains a cornerstone of effective management. Antibiotic therapy plays a crucial role in preoperative prophylaxis, postoperative treatment, and in selected cases, non-operative management of appendicitis. Cefotaxime, a thirdgeneration cephalosporin, is widely used due to its broad-spectrum antimicrobial activity, favourable pharmacokinetic properties, and clinical efficacy against common pathogens involved in appendiceal infections. This review provides an in-depth analysis of the epidemiology, pathophysiology, microbiology, pharmacology, clinical applications, safety profile, resistance concerns, and future perspectives regarding the use of cefotaxime in the management of acute appendicitis.