Keratoacanthomas are rapidly growing neoplasms of squamous epithelium. Despite their benign nature, they are often difficult to distinguish from squamous cell carcinoma and require excision. In cases in which excision is not successful or not desired, intralesional treatments may be considered. However, limited research exists on individual therapeutic efficacy. We present a 68-year-old man who developed multiple eruptive keratoacanthomas around the wound edge of a previous keratoacanthoma excision. Considering previous excisional failure, intralesional 5-fluorouracil was used as a treatment modality. Injections every 3-4 weeks over a course of 12 weeks induced clinical keratoacanthoma clearance with excellent cosmetic results. This case showcases that weekly intralesional 5-fluorouracil injections, as was the standard mode of treatment in previous case reports, may not be necessary. This less frequent injection strategy is more convenient for the patient and may lead to fewer treatments and less medication necessary. Although a case-by-case basis is needed for any alternative approach to keratoacanthoma treatment, this report is useful for the practicing clinician in showing that 5-fluorouracil may be efficacious in these difficult-to-treat patients.