The purpose of this study was to design and evaluate the performance of an Ultra-fast Disintegrating Wafer (U-D-WAF) loaded with highly water soluble diphenhydramine hydrochloride (DPH) through the oramucosa of the Large White Pig model. For the first time this work explored the oramucosivity of the U-D-WAF by detailed molecular modeling of the matrix on buccal tissue in order to mechanistically deduce the mucodhesivity. The U-D-WAF was formulated using a blend of hydroxypropylcellulose, poly(acrylic) acid, sodium starch glycolate and β –cyclodextrin in accordance with a Box-Benkhen experimental design for optimization prior to ex vivo permeation and in vivo release studies in the Large White Pig. Molecular simulation studies assess the mucoadhesivity of the U-D-WAF to the oramucosa. A mean Drug Entrapment Efficiency of 72.96 ± 4.32%, disintegration time of 29.33 ± 15.91 s and drug release after 60 s of 86.32 ± 20.37% was recorded. Ex vivo permeation studies revealed cumulative drug permeation of 86.32 ± 20.34% 60 s after onset. In vivo evaluation of the optimized U-D-WAF had a Cmax = 59 μgL−1 approximately 300 s after administration. The ultrafast disintegration of the U-D-WAF matrix with desirable mucoadhesivity in in vitro and in vivo studies makes it suitable for effective and rapid oramucosal drug delivery.