In December 2020, a major vaccination program against COVID-19 commenced in Europe with vaccines such as Pfizer’s mRNABNT162b2 (Comirnaty®). Subsequent reports of immediate and delayed skin reactions emerged. This study presents a case of a 64-year-old male who developed multiple keratoacanthomas approximately two weeks after receiving a second booster dose of the Pfizer vaccine. The patient, who had significant medical history of hypertension and diabetes, presented with erythematous, crateriform lesions on his limbs. A physical examination and histopathological analysis confirmed the diagnosis of Generalized Eruptive Keratoacanthoma (GEKA). Treatment involved cemiplimab I.v. 350 mg administered every three weeks. Within two months, the patient showed significant improvement, with the disappearance of all lesions. Dermoscopy and histopathological exams supported the GEKA diagnosis, which is a rare variant of multiple keratoacanthomas. This case suggests a potential immune-mediated mechanism triggered by the COVID-19 vaccine, leading to the rapid development of keratoacanthomas. Treatment with cemiplimab showed promise, highlighting the potential of immune checkpoint inhibitors in managing multiple keratoacanthomas. Further research is needed to explore the efficacy and safety of such treatments.