In-flight medical emergencies (IMEs) are unforeseen acute medical events, though rare demand prompt recognition and effective treatment intervention due to their unpredictable nature and high risk of dismal prognosis if not appropriately manage promptly. These emergencies pose significant challenges for cabin crew and any medical professionals mid-air due to limited medical resources onboard. These events present diversely, from syncope and seizures to dyspnea, chest pain, traumatic injuries and sudden death, often causing fear and distress among everyone onboard. Misdiagnosis can lead to inappropriate treatment intervention, poor outcomes, and costly flight diversions. Consequently, a thorough understanding of IMEs is crucial for both cabin crew and medical professionals. This requires sound theoretical knowledge, focused history-taking, a high index of suspicion, clinical skills, competencies, meticulous physical examination, clinical reasoning, investigation with point of care devices, well-defined management strategies and treatment protocols, comprehensive cabin crew training and retraining, effective use of telemedicine and technological applications, and research specific to IMEs. With growing air travel volume, an aging global population, and a rising prevalence of cardiometabolic diseases, IMEs are expected to become more frequent. This necessitates optimizing emergency responses and preparedness measures, to enhance passenger safety and reduce flight disruptions. This review explores various aspects of IMEs, including their aetiologies, pathophysiology, clinical presentation, differential diagnosis, management, and the vital roles of cabin crew and any medical professionals present, along with the pressing need for integrating training program and curricula on IMEs in medical, allied health and flight attendant institutions worldwide. Furthermore, the review underscores the importance of in-flight clinical vigilance, the supportive role of telemedicine, and the impact of onboard automated external defibrillators in improving passenger outcomes. Ultimately, strong and continuous collaboration between the medical and aviation sectors is essential for a safer travel experience for everyone.