In order to exploit the advantage of drug delivery through the buccal mucosa, mucoadhesive buccal films with propranolol hydrochloride based on polyethylene oxide, hydroxypropyl methylcellulose, and polyvinyl alcohol have been developed. The aim of this study was the development, pharmaceutical-technological (uniformity of mass and drug content, film thickness, potential interactions between polymers and propranolol hydrochloride, in vitrodrug permeation and drug release, mechanical and mucoadhesive properties), and biopharmaceutical characterization of prepared mucoadhesive buccal films through conducting in vivostudy in spontaneously hypertensive rats and in silicomodeling of intraoral and gastrointestinal drug absorption. For in vivostudy formulation F2 (hydroxypropylmethyl cellulose 0.5%, polyethylene oxide 3.5%, polyvinyl alcohol 1.5%, propylene glycol 3%, and propranolol hydrochloride 2%) was selected, which showed the highest values of tensile strength and percentage of elongation, as well as the highest value of the force of adhesion. Results of pharmacokinetic in rats and in silicomodeling confirmed the superiority of the mucoadhesive buccal films over immediate-release tablets (in rats: AUC0→24h66.13 ± 18.03 vs. 24.61 ± 5.52 μg⋅h/mL, AUC0→∞111.82 ± 39.04 vs. 47.85 ± 11.67 μg⋅h/mL; in silico: AUC0→24h200.17 vs.74.58 ng⋅h/mL, AUC0→∞204.04 vs. 75.64 ng⋅h/mL). Hemodynamic measurements have shown that mucoadhesive buccal films, compared to immediate-release tablets, provide a more pronounced decrease primarily in heart rate (28-51%), but also in diastolic pressure (up to 33%), as well as a longer heart rate reduction that was maintained for up to 12th h. Therefore, mucoadhesive buccal films increased the degree of absorbed drug and thus contributed to better therapeutic outcomes compared to immediate-release tablets for peroral administration.