To evaluate the efficacy of intra-alveolar administration of dexamethasone 4 mg in the control of edema, trismus, and pain resulting from the extraction of impacted lower third molars and the drug permeability through the oral mucosa by in silico prediction. The randomized, double-blind, split-mouth clinical trial included patients who had both impacted lower third molars in equivalent positions. Hemiarches were divided into control side when dexamethasone was administered orally and experimental side when dexamethasone was administered using the intra-alveolar route. Patients were evaluated considering edema, trismus, and pain. The permeability of dexamethasone through the oral mucosa was assessed by in silico prediction. Student?s t-test was selected for comparative analysis of edema and trismus, and the chi-square test analyzed the distribution of postoperative pain between the sides. There were no significant differences between the routes of administration in measuring symptoms between the pre and postoperative times (p>0.05). In silico prediction suggested that dexamethasone molecular characteristics facilitate intra-alveolar administration. Intra-alveolar administration had similar efficacy to oral administration in controlling symptoms of post-surgical inflammation of impacted lower third molars.