The objective of the study was to evaluate the sorption of a pool of pharmaceutically active compounds (PhACs) onto a clay–sand filter in a dynamic sorption experiment. The chosen adsorbent should have suitable chemical properties for the removal of the targeted PhACs and also a consistent hydrodynamic behavior regarding field application. In this aim, the impact of interfoliar cations (Ca²⁺ or Na⁺) intercalated into natural montmorillonite (Swy2) was tested by using different clay–sand ratios (from 0% to 100% of clay minerals). Only Ca-Swy2 showed a consistent hydraulic conductivity for field application with a value of 4.78 × 10⁻⁸ m s⁻¹ for a 5%/95% clay–sand ratio. The sorption of PhACs onto this filter was investigated using œdometer cells by varying two parameters: the solution matrix (ultra-pure water or natural effluent) and the injection pressure (0.1 MPa and 0.2 MPa). The PhACs were effectively adsorbed onto the filter for each experiment at different levels. The drop in injection pressure was a favorable factor for sorption whatever the matrix was, with median global removal of ∼45% at 0.2 MPa and ∼75% at 0.1 MPa. The effect of the matrix exhibited two different trends as a function of the molecular charge of each PhAC. While cationic compounds were more effectively sorbed in the ultra-pure water matrix than in the effluent matrix, the sorption of anionic PhACs was more effective in the effluent matrix than in ultra-pure water. This indicates that the charge of the pollutant is a key parameter in controlling the efficiency of the adsorbent. Despite these removal variations, the filter exhibited a significant sorption capacity especially at 0.1 MPa. It can therefore be an efficient solution for the removal of PhACs by tertiary filtration.