UV-vis spectra of anionic ibuprofen and naproxen in a model lipid bilayer of the cell membrane are investigated using computational techniques in combination with a comparative analysis of drug spectra in purely aqueous environments. The simulations aim at elucidating the intricacies behind the negligible changes in the maximum absorption wavelength in the experimental spectra. A set of configurations of the systems constituted by lipid, water, and drugs or just water and drugs are obtained from classical Molecular Dynamics simulations. UV-vis spectra are computed in the framework of atomistic Quantum Mechanical/Molecular Mechanics (QM/MM) approaches together with Time-Dependent Density Functional Theory (TD-DFT). Our results suggest that the molecular orbitals involved in the electronic transitions are the same, regardless of the chemical environment. A thorough analysis of the contacts between the drug and water molecules reveals that no significant changes in UV-vis spectra are a consequence of ibuprofen and naproxen molecules being permanently microsolvated by water molecules, despite the presence of lipid molecules. Water molecules microsolvate the charged carboxylate group as expected but also microsolvate the aromatic regions of the drugs. © 2023 American Chemical Society.