Smart polymeric matrices based on 2-vinyl pyridine (2-VPY) and three different crosslinkers: ethylene glycol dimethacrylate (EGDMA), divinylbenzene (DVB), and trimethylolpropane trimethacrylate (TMPTMA) were prepared either by the imprinting technique of the tramadol molecule or conventionally by the free radical polymerization process. The polymers were used as sorbent materials for tramadol from its solutions. The polymers prepared by the imprinting technique demonstrated superior absorption of tramadol molecules than those prepared by the conventional method. The two sorbent materials constructed from TMPTMA, regardless of the method, achieved the highest absorption capacity compared with those prepared from EGDMA or DVB. It was found that loaded imprinted polymer released more tramadol than loaded nonimprinted polymer in all media. In the acidic medium, the protonation of the nitrogen atom in the pyridine ring ionized the chains and expanded the loaded pores leading to the rapid release over the neutral and alkaline media. Additionally, the isothermal studies of MIP3 and NIP3 were extremely fitted to Freundlich adsorption and the (D-R) isotherm, respectively, while the kinetic studies of both sorbents were fitted to the pseudo-second-order model.