Medical emergencies during short- or long-haul commercial airline flights have become more commonplace due to the aviation industry's contemporary growth, the popularization of commercial flights, and an increased aging of air travelers with significant comorbidities. However, the precise incidence of onboard medical events on commercial airlines and the most common medical conditions is unclear. In this systematic review and meta-analysis, we explored the incidence of in-flight medical emergencies among airline passengers and estimated the incidence rate by physiological body system, or organ class/syndrome for emergencies that may be associated with different body systems. We limited our search to cohort studies published between 1945 to October 31, 2020 in MEDLINE, Embase, Cochrane Library and official reports from the Federal Aviation Administration/International Air Transport Association, regardless of the language of publication. Only studies that evaluated the overall frequency of onboard medical events on commercial air carriers (in which they also presented the total number of annual revenue passengers) and the frequency of events by physiological body systems or organ class/syndrome were included. We excluded case reports and case series, systematic or narrative reviews, and studies addressing specific health-related conditions. Two independent investigators performed first- and second-phase study screening, abstracted data, and appraised risk of bias. We rated the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Using a quality effect model, we meta-analyzed data associated with the incidence of in-flight medical emergencies, all-cause fatality, incidence of medical events by medical condition category, frequency of en-route diversion, presence of medical personnel on board, and the use of an automatic external defibrillator. We also extracted data regarding the cost of flight diversion. Of 18 individual studies with approximately 1.5 billion passengers, 11 reported the overall incidence of in-flight medical emergencies. Low certainty of evidence suggested that the global incidence of in-flight medical emergencies was 18.2 events per million passengers (95% CI 0.5 to 53.4 per million; I2 = 100%, P < 0.001, very low certainty), and an all-cause mortality rate was 0.21 per million passengers (95% CI 0 to 0.76 per million; I2 = 99%, P < 0.001, low certainty). The four most common categories of medical conditions or syndromes during flight were syncope, gastrointestinal events, respiratory and neurological diagnostic groups. The diversion rate was 11.1 per 100,000 flights (95% CI 5.9 to17.6 per 100,000 flights; I2 = 97%, P < 0.001), with an average cost ranging from $15,000 to $893,000 per unplanned emergency landing across studies which examined this outcome. In-flight medical events on commercial travels are extremely low with a corresponding very low in-flight mortality rate. Associated costs derived from en-route diversion might significantly influence airlines' budgetary equilibrium. Novel and modern standardized reporting systems or platforms should be internationally provided and enforced by health and aviation authorities to obtain higher quality patient-passengers datasets. Onboard volunteer medical providers must be aware of everyday life-threatening events during commercial flights and should consider the establishment of a connection between the aircraft and ground-based medical advisory services while assisting in-flight medical events.