<p>Selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are widely used for managing chemotherapy-induced, post-operative, and radiation-induced nausea and vomiting. The 5-HT3 receptor, a ligand-gated ion channel in the nervous system, regulates vomiting and gastrointestinal motility. Selective antagonists like ondansetron, granisetron, and tropisetron treat chemotherapy and post-surgical nausea, while non-selective antagonists include metoclopramide and prochlorperazine. Despite their efficacy, a critical safety concern is the potential for prolonging the QT interval, which can predispose patients to life-threatening arrhythmias such as torsades de pointes, particularly in those with congenital long QT syndrome. This risk has led to FDA dosing recommendations and an emphasis on cardiac monitoring, particularly in patients with predisposing factors such as electrolyte imbalances, cardiac conditions, or concurrent QT-prolonging drugs. This review explores the underlying mechanisms of QT-interval prolongation associated with the selective 5-HT3 receptor antagonist ondansetron, evaluates its impact on morbidity and mortality in at-risk populations, and discusses risk mitigation strategies.</p>