A bilayered mucoadhesive buccal film containing a combination of ornidazole (OD) and dexamethasone sodium phosphate (DEX) was prepared using solvent casting to treat oral ulcers. Films were systematically evaluated in vitro to obtain the optimum formulation. The therapeutic effects of these films were investigated in the rabbit oral ulcer model and the in vivo release of OD and DEX in the human oral cavity was also evaluated. The backing layer contained ethyl cellulose and an optimal mucoadhesive layer containing both OD and DEX was produced. Films from the optimum formulation were 0.427 ± 0.015 mm thick, weighed 55.89 ± 0.79 mg, and had a surface pH of 6.34 ± 0.01. The drug content of the optimum formulation approximated the theoretical value with good uniformity (2.959 ± 0.106 mg/cm2 for OD and 0.877 ± 0.031 mg/cm2 for DEX). The formulation showed favorable swelling characteristics and both drugs were released at >95% after 4 h. Moreover, the compound film had a statistically significant effect on mucosal repair and reduced ulcer inflammation without stimulating the human oral mucosa. Cmax of OD in saliva was 37.04 μg/ml and that of DEX was 9.737 μg/ml. Given promising therapeutic effects, the compound film developed here could become a local drug delivery device for treating oral ulcers.