Oral potentially malignant disorder (OPMD) is associated with an increased risk of progression to oral cancer. Patients with dysplastic changes of the precancerous lesions have a higher malignant transformation rate than those without dysplastic changes. Radiotherapy and surgery are the traditionally preferred choices for OPMD treatment. However, side effects caused by radiotherapy and surgery may reduce the willingness of patients to accept therapy. Therefore, developing an Orabase-formulated drug, which can be non-invasively administered, may provide an alternative treatment choice. To find, verify, and develop a new anti-cancer drug cost a lot of time and money, while drug repurposing can shorten both time and cost. In this study, we utilized high-throughput screening library to identify clinical drugs, which may have new bioactivities. Herein, we report that benzalkonium chloride (BAK), an antimicrobial preservative for pharmaceutical products, significantly induced reactive oxygen species production and cell death in oral precancerous cells. Additionally, our results showed that phosphorylation of STAT3 (Tyr705) and Akt (Ser473) were involved in cell death caused by BAK in DOK cells. According to animal studies, the development of DMBA-induced oral precancerous lesions was inhibited by 2% BAK. In conclusion, Orabase-formulated BAK may be a potential treatment for OPMD in the future.