Bioavailability of lipid nutrients depends on a complex physicochemical and enzymatic process: digestion by lipases in the stomach then the intestine, uptake by the enterocytes and transport towards the user cells. Physiological (newborn infants, aged people) or pathological (cystic fibrosis, pancreatitis) impairment of this process reduces the bioavailability of the essential fatty acids, which are required for development and functioning of body cells. This manuscript presents strategies for improving lipid nutrients bioavailability in subjects suffering from pancreatic insufficiency, by using the physicochemical properties of lipids. Indeed, they determine major characteristics of the lipid interface (area, compounding), where enzymatic hydrolysis occurs. Our work shows, in vitro under conditions close to physiology, that the type of phospholipid entering the composition of a triolein emulsion, or the addition of a certain type of free fatty acid in the lipid mixture before emulsification, modifies the size and zeta potential of the lipid droplets, influences the action of gastric, pancreatic and bile salt-stimulated lipases, and modulates fatty acid absorption by Caco-2 cells. A large effect is obtained with the lysophosphatidylinositol, making this lipid molecule potentially usable in clinical nutrition. It presents an amazing interfacial behavior (molecular area, compressibility) and its mechanism of action associates indirect effects (modifications of the lipid interface) and direct ones (interactions with lipases).