Instantly dissolving buccal films have gained attention owing to their easy administration and capability to surmount the hepatic first pass effect of drugs. Dapoxetine hydrochloride (DPX) has a low oral bioavailability due to significant hepatic first pass metabolism. In addition, DPX is a weakly basic drug with a pH dependent solubility that could limit its dissolution in the body neutral fluids. In order to surpass these challenges, this work aimed at enhancing DPX bioavailability via the formulation of instantly dissolving buccal films comprising a pH modifier and a hydrophilic cyclodextrin. Tartaric acid and hydroxypropyl beta-cyclodextrin were selected as dual solubilizing agents based on the screening study. 32 factorial design was employed for the formulation and optimization of DPX films. Statistical analysis revealed that hydroxypropyl methyl cellulose E5: maltodextrin ratio and propylene glycol concentrations have significant effects on mechanical properties, percent DPX dissolved after 5 min, and in vivo mouth dissolving time at P < 0.05. The optimized film [HPMC E5: MDX, 1:1 and 1% PG] showed no significant change of properties or drug dissolution upon storage at 40 °C/75% RH for a period of 3 months. In addition, the optimized film showed significantly enhanced absorption relative to the oral reference tablet. Therefore, the optimized film could be considered a promising delivery system for DPX with expected improved patient compliance and enhanced pharmacokinetic performance.