The pharmaceutical products for local oral/buccal cavity treatments are limited and unsatisfactory. Herein, we developed and characterized the hydroxypropyl methylcellulose (HPMC, grade K100M, viscosity of 75,000–140,000 cps) microparticles for the local administration and disease treatments in the oral cavity. Ibuprofen was used as a model drug. First, using the desolvation method, with varied factors, the optimal formulation condition included (1) the initial ibuprofen amount of 60 mg, (2) the stirring time of 60 minutes, (3) the stirring temperature of 25°C, (4) the centrifugal time of 10 minutes, and (5) the centrifugal speed of 6,000 rpm, which yielded particles with a size of 13.47 ± 0.32 μm, a rapid swelling property, the drug entrapment efficiency of 61.23% ± 1.04%, and the weak interactions between ibuprofen and HPMC. Second, compared with the free drug aqueous suspension, the ibuprofenloaded HPMC microparticles showed a sustained release pattern with a maximum release amount of nearly 100%. Lastly, the particles possessed high mucoadhesive properties in the ex vivo test using the buccal mucosa. In summary, proven by the case of ibuprofen, the HPMC microparticles showed the potential to be a novel mucoadhesive drug delivery system.