A new approach to the computational design of molecularly imprinted polymers (MIP) specific for ephedrine is presented. A virtual library of functional monomers was developed and screened against the template using molecular modelling software. The monomers giving the highest binding score were co-polymerized with a cross-linker in the presence of ephedrine. Control (blank) polymers were prepared under the same conditions but in the absence of the template. A good correlation was found between the modelling results and performance of the materials in an HPLC study. A MIP based on one of the selected monomers—hydroxyethyl methacrylate—gave a separation of ephedrine enantiomers with a separation factor α of 1.42–2.09 (depending on temperature). This figure is larger than the α values generally obtained with commercially available chiral phases. It is anticipated that the computational approach will be of use for the rational design of MIPs and the prediction of polymer affinity and specificity.