Aiming to improve the sensitivity and specificity of environmental analysis of sertraline residues, we investigated the use of molecularly imprinted polymers (MIPs) as the solid phase extraction sorbents for rebinding of the parent drug, its metabolite norsertaline and its transformation product (TP) sertraline ketone. MIPs were synthesized using the antidepressant sertraline as the target, where two polymerisation approaches were used: polymerisation in solvent and two-stage polymerisation. Leaching of sertraline from the imprinted material presented a major problem in case of MIPs polymerised in solvent. On the contrary, by synthetizing MIPs with the two-stage polymerisation approach, sertraline was removed to below the limit of quantification (LOQ). Two MIPs were selected that showed the best binding characteristics during the solid phase extraction rebinding experiments: one was prepared by polymerisation in solvent and another one by two-stage polymerisation. The former bound norsertraline and sertraline ketone in a high binding ratio compared to its non-imprinted analogue, while the latter had the highest imprinting factor for sertraline. Based on the proved cross-selectivity of MIPs, we propose their use in enrichment, purification and isolation of transformation products, including novel compounds that have before not been recognised.