An improved understanding of the behaviour of lipids within the gastrointestinal tract will facilitate the structural design of foods that provide specific physiological responses. In this work, we studied the influence of interfacial characteristics (emulsifier type and surface area) on the behaviour of emulsified lipids within a simulated small intestine (duodenum). Pluronic F68-stabilized emulsions were more resistant to lipid digestion than lecithin-stabilized emulsions. Interfacial tension, droplet charge (ζ-potential), and microstructure measurements were used to identify the physicochemical origin of this effect. Pluronic F68 was shown to be more difficult than lecithin to displace from lipid droplet surfaces by bile salts and lipase arising from the duodenal juice. Specifically, duodenal components decreased the interfacial tension of a Pluronic-covered interface to a lesser extent, as compared to the interface covered by lecithin. These results demonstrate that the properties of the interfacial layer surrounding lipid droplets can be designed to modulate the lipid digestion process. This knowledge is critical for the rational development of delivery systems for food and pharmaceutical applications that can control the uptake of lipids and lipid-soluble components under physiological conditions.