This study aims to reveal the potential of using pomegranate seed (PS) as an alternative, new and cost-effective adsorbent for the removal of anionic dyestuffs such as Congo Red (CR) and Remazol Brillant Blue R (RBBR) from aqueous solutions. In addition, the PS was activated by a high-energy planetary ball milling. It was seen that the activated PS (APS) has a higher adsorption capacity and mechanical activation has a positive effect on the adsorption process. The effects of experimental factors were evaluated using both conventional univariate methods and multivariate methods such as response surface methodology (RSM) approach. The effects of experimental factors and possible interactions on both dyestuff removal and adsorption capacity were expressed in mathematical equations. The removal efficiencies over 90% were achieved for both dyestuffs at optimum conditions determined by central composite design (CCD). As a result of isothermic, kinetic, and thermodynamic evaluations, the nature of adsorption was best explained by the Temkin isotherm model and the adsorption mechanism was defined as a chemically controlled, exothermic, and spontaneous reaction. The functional groups and the morphological properties of the adsorbent were determined by Fourier transform infrared spectrophotometry (FTIR) and scanning electron microscopy (SEM) in order to explain the possible interactions between adsorbent and adsorbent molecules.