Mass gatherings (MGs) have been associated with high rates of morbidity and mortality from non-communicable diseases, accidents, and terrorist attacks, thus posing complex public health challenges. We assessed the health risks and public health responses to MGs to identify an evidence-based framework for public health interventions. Human stampedes and heat-related illnesses are the leading causes of mortality. Minor traumatic injuries and medical complaints are the main contributors to morbidity and, particularly, the need for onsite medical care. Infrastructure, crowd density and mood, weather, age, and sex determine the risks to health. Many predictive models for deployment of medical resources are proposed, but none have been validated. We identified the risks for mortality and morbidity during MGs, most efficient public health interventions, and need for robust research into health risks for non-communicable diseases during MGs.