INTRODUCTION AND IMPORTANCE: Cyclophosphamide is a widely used immunosuppressant for inducing remission in various immune-mediated conditions. However, its potential for cardiotoxicity is well documented. One of the earliest possible manifestations of this cardiotoxicity following cyclophosphamide infusion is atrial fibrillation (AF), which typically presents within 48 h of the infusion. CASE PRESENTATION: The authors present a case of a 58-year-old male with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis who presented to the emergency department with clinical features of acute kidney injury. Following subsequent assessment and evaluation, the patient was managed in the intensive care unit with hemodialysis and intravenous corticosteroids. He was aimed at inducing remission with cyclophosphamide infusion. However, a few hours following induction with cyclophosphamide infusion, the patient developed palpitation, sweating, and tachycardia with a heart rate of 140-180/min. The electrocardiogram showed an irregular QRS complex with an absent p-wave. AF was diagnosed and managed with amiodarone infusion for 24 h followed by oral maintenance dosing. No further episode of AF occurred following cessation of cyclophosphamide and switching to rituximab for the treatment of ANCA-associated vasculitis. CLINICAL DISCUSSION: Cyclophosphamide, even at lower dosages, can cause cardiotoxicity in patients with renal impairment due to the delayed elimination of its toxic metabolites. In addition, patients who receive CYP 450 inducers, such as prednisone, may experience the accelerated build-up of its toxic metabolites, thereby raising the risk for cardiotoxicity. CONCLUSION: The cardiotoxic manifestation of cyclophosphamide can arise from its use in several immune-mediated conditions. Given its potential for cardiotoxicity, careful cardiac monitoring during and after cyclophosphamide infusion is essential to ensure timely intervention, if needed.