Phenyl-functionalized mesoporous silica materials were used to explore the effect of non-covalent interactions on the release of Ibuprofen into simulated body fluid. Variations in orientation and conformational mobility of the surface phenyl groups were introduced by selecting different structural precursors: 1) a rigid upright orientation was obtained using phenyl groups directly bound to surface Si atoms (Ph-MSN), 2) mobile groups were produced by using ethylene linkers to connect phenyl groups to the surface (PhEt-MSN), and 3) groups co-planar to the surface were obtained by synthesizing a phenylene-bridged periodic mesoporous organosilica (Ph-PMO). The Ibuprofen release profiles from these materials and non-functionalized mesoporous silica nanoparticles (MSN) were analyzed using an adsorption-diffusion model. The model provided kinetic and thermodynamic parameters that evidenced fundamental differences in drug-surface interactions between the materials. All phenyl-bearing materials show lower Ibuprofen initial release rates than bare MSN. The conformationally locked Ph-MSN and Ph-PMO have stronger interactions with the drug (negative Delta G of adsorption) than the flexible PhEt-MSN and bare MSN (positive Delta G of adsorption). These differences in strength of adsorption are consistent with differences between interaction geometries obtained from DFT calculations. B3LYP-D3-optimized models show that pi-pi interactions contribute more to drug adsorption than H-bonding with silanol groups. The results suggest that the type and geometry of interactions control the kinetics and extent of drug release, and should therefore serve as a guide to design new drug delivery systems with precise release behaviors customized to any desired target.