During health emergencies, non-pharmaceutical interventions (NPIs) are adopted in various combinations until a vaccine can be produced and widely administered. Containment strategies, including the closure of schools, churches, and dance halls; banning of mass gatherings; mandatory mask wearing; isolation; and disinfection/hygiene measures, require reasonable compliance to be successfully implemented. But what are the most effective measures? To date, few systematic studies have been conducted on the effects of various interventions used in past epidemics/pandemics. Important contributions to our understanding of these questions can be obtained by investigating the historical data from the great influenza pandemic of 1918, an event widely considered one of the greatest natural disasters in human history. Taking on particular importance is the study of the possible role played by the behaviour of the population and the lack of public obedience to the non-pharmaceutical interventions in a Mediterranean country like Italy—one of the most affected countries in Europe—during that pandemic, with special attention paid to the weight of the socio-cultural factors which hindered the ultimate goal of containing the spread of the virus and preventing excess deaths in the country.