The aim of this study was to develop a controlled release drug-in-adhesive patch containing escitalopram (ESP) using ion-pair technique. Special attention was paid on the mechanism of how counter ion controlled the release of ESP. Five organic acids were chosen as the counter ions. Formulation factors including adhesive matrix, drug loading and permeation enhancers were investigated through in vitro experiments using rat skin and the optimized patch was evaluated using in vivo pharmacokinetic study. Drug-counter ion-PSA interactions were characterized by FT-IR, molecular modeling and DSC at molecular level. The optimized patch prepared with ESP-BA showed zero-order skin permeation profile and a satisfied permeation amount of three days (1059 ± 104.9 μg/cm2) in vitro, which also showed a steady-state drug plasma concentration lasting 36 h in vivo and the Cmax was significantly controlled compared with the control group. The controlled release of ESP was attributed to the interactions among ESP-counter ion-PSA by hydrogen bonding, and counter ion enhanced the interaction between ESP and PSA molecule, which acted as a “bridge” between them. In conclusion, a controlled release ESP transdermal patch was developed and a novel insight of ion-pair controlled release was proposed at molecular level.