Computational studies in implicit solvent revealed an increasing energetic cost for hydroxide over chloride in the macrocycle, resulting in a reduction in relative binding preference for OH -observed in the acyclic structure. Furthermore, MD simulations in POPC membrane in explicit solvent enabled the evaluation of the binding-induced desolvation of the anions at the membrane interface. This analysis revealed that anion encapsulation at the binding site reduces the solvation around both ions and consequently increases the dehydration penalty, with the effect being more pronounced for hydroxide. The reduction in hydroxide binding preference and enhanced desolvation effects induced by the halogen bonding macrocyclic structure together contribute to the overall high chloride over hydroxide selectivity. We anticipate that the novel halogen-bonding macrocyclic scaffolds, along with the computational rationalisations of their high selectivity, may inform the development of future highly selective transporters for translational applications in medicine.