MCM-41 type mesoporous silicates were functionalized with nickel species via thermal monolayer and grafting techniques, respectively. The material potential to serve as sorbents for the selective removal of a pharmaceutical drug (i = Naproxen) from water was tested via single component adsorption equilibria measurements at ambient conditions and Ci = 18 ppm. In general, the grafting technique provided the best strategy to avoid metal leaching. Although the anchoring of the nickel species was successfully accomplished, analysis of the textural properties of the resulting sorbent indicated that a considerable reduction in average pore size (ca. 1 nm), and hence surface area, limited the ultimate uptake capacity. Nevertheless, after normalization with respect to accessible surface area, the grafted sorbents offered capacities comparable to those exhibited by a traditional activated carbon (0.42 vs. 0.67 μmol/m²). Ab initio and density functional theory calculations were employed to estimate the surface interaction energies for single sorbent clusters and attempt to describe the adsorption mechanism. Full optimization of the structures showed that the sorbate–sorbent interactions were at the weak-chemisorption level (~15 kcal/mol), which is suitable for ultrapurification applications and sorbent regeneration via simple engineering means. In addition, a natural bond orbital analysis indicated that the interaction between the Naproxen and the nickel functionality results in a redistribution of electrons within the most prominent orbitals in the transition metal center (i.e., 4s and 3d). This suggests that the interaction between sorbate and sorbent could generate a metal complex, but further studies are required to validate this hypothesis and to determine a sorbent regeneration strategy.