The aim was to investigate the effect of constant current iontophoresis on the delivery and biodistribution of buflomedil hydrochloride (BUF) in the buccal mucosa. Quantification was by UHPLC-MS/MS; in addition to total delivery, the amounts present in the epithelia and the lamina propria (the target tissue) were also determined. Two-compartment vertical diffusion cells were used to investigate the effect of current density (0.5, 1 and 2 mA/cm2), application time (5, 10 and 20 min) and concentration (5, 10 and 20 mM) on iontophoretic delivery of BUF from aqueous solutions. In contrast to passive delivery, iontophoresis for 10 min at 1 mA/cm2 resulted in statistically equivalent transport from a 20 mM solution and a 2% HEC hydrogel (with equivalent BUF loading; 20 µmol). BUF delivery from the hydrogel using diffusion cells and a new coplanar "side-by-side" set-up was statistically equivalent (304.2 ± 28.9 and 278.2 ± 40.3 µg/cm2) - passive delivery was also similar. Iontophoresis (10 min at 1 mA/cm2) using a thin film (20 µmol BUF) was superior to the passive control (323.3 ± 5.9 and 24.8 ± 5.9 µg/cm2). Concentrations in the LP were ~700-fold > IC50 to block collagen production, potentially providing a new therapeutic strategy for oral submucous fibrosis.