Odontogenic keratocysts (OKCs) are developmental cysts that originate from cellular remnants of the dental lamina and are characterized by a high rate of post-surgical recurrence. Chemical adjuncts such as Carnoy’s solution or cryotherapy can lower recurrence but introduce risks such as neurotoxicity and bone necrosis. Topical 5-fluorocuracil (5-FU) has emerged as an alternative, typically delivered over a 24-hour period on ribbon-gauze packing, which requires patient compliance with close post-operative follow-up. This case describes using a short-interval, intraoperative, 5-FU application as an adjunct to standard surgery. A left-sided mandibular body OKC in a 75-year-old male was treated with enucleation and curettage plus peripheral ostectomy. A 5% 5-FU cream was applied on cotton applicator tips to the cyst cavity and allowed to dwell for less than 15 minutes, followed by copious saline irrigation and suction to remove. The defect was then grafted with particulate corticocancelleous allograft and a resorbable membrane, and then primary closure was obtained. Serial imaging demonstrated progressive bone fill at 2 months and 15 months post-surgery with no clinical or radiographic evidence of recurrence. A short-interval 5-FU protocol may capture the anti-proliferative benefits of 5-FU while avoiding the patient inconvenience and risks associated with leaving packing material in a surgical site. This case demonstrates that a less than 15-minute application of 5-FU can be safely integrated with peripheral ostectomy and grafting in the successful treatment of OKCs. Prospective studies with larger cohorts and longer surveillance are warranted to compare recurrence, morbidity, and cost-effectiveness against 24-hour 5-FU protocols.