Topical oral sprays are frequently used to prevent and manage oropharyngeal inflammation and lesions. This study investigated the histopathologic changes noted in the oral mucosa of mice after topical application of 3 widely prescribed antibacterial products. The 25 animals were divided into 5 groups and treated for 10 days with 2 sprays daily, as follows: group 1-chlorhexidine gluconate 0.12% + benzydamine hydrochloride 0.15%; group 2-benzydamine 0.27 mg/0.18 mL x 30 mL; group 3-chlorhexidine 0.2%; group 4-fusafungine 1%; and group 5 (cohort)-physiologic serum. On day 10 after drug administration, biopsy specimens were taken from the oropharyngeal mucosa of the tongue, the cheek mucosa, and the tongue base; these were examined under a light microscope and were classified as normal or pathologic. All topical oral sprays produced some degree of histopathologic change, such as hyperplasia, fibrosis, low-grade dysplasia, congestion, or edema. The local irritant effects of topical oral sprays should be considered when treatment is selected for patients with oropharyngeal disorder.