The coronavirus disease (COVID-19) has brought significant social and economic disruptions and devastating impacts on public health, and vaccines are being developed to combat the disease. Timely vaccination may prevent complications and morbidity but may also potentially result in unforeseen outcomes in some special clinical populations. We report on a case of hypersomnia relapse after the COVID-19 vaccination, with the aim of informing the development of the guideline on vaccination in specific groups. A 19-year old female presented with persistent daytime sleepiness after receiving the COVID-19 vaccine. She had a known history of hypersomnia secondary to infectious mononucleosis but has fully recovered for 8 months. A series of examinations were performed on this patient. Neurologic and psychiatric examinations were unremarkable. Despite normal nocturnal subjective sleep quality (Pittsburgh Sleep Quality Index score = 5, Insomnia Severity Index score = 7), her Epworth sleepiness scale score (15) suggested an abnormal level of subjective sleepiness. Consistent with the subjective report, the objective assessment by Multiple Sleep Latency Test found mean sleep latency was 1.3 min with no sleep onset rapid-eye-movement (REM) period. We speculate that COVID-19 vaccine may potentially trigger the relapse of hypersomnia. The immune memory could be an explanation for the increased response to vaccine in patients with secondary hypersomnia. Caution should be warranted when administering COVID-19 vaccine in patients with hypersomnia secondary to infections.