Objective: Labetalol hydrochloride is an alpha/beta adrenoceptor blocker that undergoes comprehensive first pass-metabolism resulting in a low oral bioavailability. This study aimed to formulate and evaluate mucoadhesive buccal formulations of labetalol hydrochloride for enhancement of its bioavailability. Methods: Using various concentrations of hydroxypropyl methylcellulose (HPMC), carbopol-934, and sodium alginate, ten formulations of mucoadhesive buccal tablets containing labetalol hydrochloride were prepared. The produced tablets were evaluated to test physical and mucoadhesive properties as well as in-vitro drug release properties. Ex-vivo evaluations of the tablets were examined using chicken pouch membrane. Formulations that offered best results in in-vitro and ex-vivo evaluations were selected for running in-vivo comparative bioavailability study using New Zealand rabbits and adopted HPLC method to assess the buccal bioavailability of labetalol hydrochloride in relation to its oral bioavailability from commercial tablets. Results: It was found that drug release and mucoadhesive properties depended on the type and proportion of different polymers. Sodium alginate-containing formulations showed higher release rates and ex-vivo permeation rates compared to carbopol-containing formulations. Increasing the proportion of HPMC resulted in more swelling, better mucoahesion forces and times but more delayed permeation and release rates. A strong correlation was detected between in-vivo drug release and ex-vivo transmucosal permeation of labetalol hydrochloride. The relative bioavailability of labetalol hydrochloride from the selected mucoadhesive buccal tablets F1 and F6 were 2.76 and 1.60, respectively. Conclusion: The produced mucoadhesive buccal tablets were successful in improving the systemic bioavailability of labetalol hydrochloride in rabbits. Clinical applications of formulations F1 and F6 are recommended.