Seal area represents the most problematic part in food packaging for controlling the moisture and gas ingress and preserving product quality. Understanding the mechanism of heat sealing, which is a widely used method in flexible packaging, is critical for maintaining product quality throughout the storage and preventing food waste. Likewise, understanding the factors causing the leak formation in the seal interface helps to avoid failures and increase integrity for all seal types produced by heat sealing methods. This review looks at heat sealing and its mechanisms in flexible food packaging materials and particularly focuses on the reasons behind the encountered seal integrity problems that have a detrimental effect on food quality and shelf life. Heat sealing mechanisms, form fill seal systems and seal types were analyzed. Then, factors affecting the leak formation have been grouped as process parameters, material properties, contaminants, and further processes, which is uncharted territory in open literature. Finally, the details of these groups and their interrelationships were examined and discussed. Revealed key factors as shown in this study are expected to guide future research for understanding leak formation mechanisms in flexible food packaging.