The present study investigates the molecular mechanisms of polyphenol-lipid interactions and their impact on membrane properties. Using pyrene and DPH as reporter molecules, we examined the impact of quercetin, curcumin, gallic, and salicylic acids on membranes composed of phosphatidylcholine (PC) and its mixtures with phosphatidylglycerol (PG), cardiolipin (CL), and cholesterol (Chol). Quercetin was found to increase the lipid order without affecting the lipid bilayer free volume, indicating interactions near the membrane surface. In turn, curcumin exhibited more complex effects, reducing free volume in PC but increasing it in PG vesicles, reflecting its amphiphilic structure and variable penetration depth. Gallic and salicylic acids selectively increased free volume at the membrane core without influencing lipid order at the upper regions of lipid bilayer. The results obtained demonstrate that polyphenol structure and lipid composition dictate the resultant pattern of polyphenol-membranes interactions, which may have implications for drug delivery and nutraceutical design.