An experimental design was established in order to optimize the mechanical properties of two oral film formulations intended for oral delivery of bioactive compounds. Carboxymethylcellulose (CMC) and gelatin type A (GelTA) were selected as polymeric matrix. Scanning electron microscopy revealed that caffeine crystals were homogeneously dispersed onto oral film matrix. Fourier-transform infrared analysis did not indicate formation of new chemical entities. USP modified dissolution assay revealed that GelTA was more effective in controlling caffeine release since maximum caffeine release (97.4% ± 0.95) after 20 min. On the other hand, CMC is better indicated for immediate release since maximum caffeine release (81.1% ± 2.14) occurred after 4 min. Simulation of gastrointestinal tract with ex vivo permeability assay was in accordance with USP dissolution assay (42.0% ± 7.79 and 15.3% ± 4.0 of caffeine released from CMC and GelTA oral films (OF), respectively, permeated porcine intestinal mucosa after 120 min). CMCOF and GelTAOF optimized formulations represent two suitable oral delivery systems for immediate and controlled release, respectively.