We report the synthesis and characterization of a novel photo-switch based on biomimetic cyclocurcumin analogous and interacting with the lipid bilayer, which can be used in the framework of oxygen-independent light-induced therapy. More specifically, by using molecular dynamics simulations and free energy techniques, we show that the inclusion of hydrophobic substituents is needed to allow insertion in the lipid membrane. After having confirmed experimentally that the substituents do not preclude the efficient photoisomerization, we show through UV–vis and dynamic light scattering measurements together with compression isotherms that the chromophore is internalized in both lipid vesicles and monomolecular film, respectively, inducing their fluidification. The irradiation of the chromophore-loaded lipid aggregates modifies their properties due to the different organization of the two diastereoisomers, E and Z. In particular, a competition between a fast structural reorganization and a slower expulsion of the chromophore after isomerization can be observed in the kinetic profiles recorded during E to Z photoisomerization. This report paves the way for future investigations in the optimization of biomimetic photoswitches potentially useful in modern light-induced therapeutic strategies.