Glandular odontogenic cyst (GOC) is a rare, aggressive odontogenic lesion that presents in the jaws. It is a diagnostically challenging entity due to its ability to mimic intraosseous mucoepidermoid carcinoma, botryoid cyst, surgical ciliated cyst, and radicular cyst. Treatment ranges from conservative to aggressive surgical interventions due to its varied clinical and radiological appearance and also its potential for recurrence. Aggressive surgical interventions result in the need for surgical site reconstruction, thus increasing patient morbidity. We report a case of GOC in the anterior mandible that was conservatively treated by the application of 5-Fluorouracil (5-FU). Topical application of 5-FU was selected in the management of this lesion as it has shown to be effective in reducing recurrence rates of other aggressive odontogenic lesions such as odontogenic keratocysts. To our knowledge, this is the first case reported in the literature that was successfully treated by the combination of cyst enucleation, curettage, peripheral ostectomy and application of 5-FU. No recurrence was detected after 14-month follow-up.