We report the case of a previously healthy 69-year-old female who developed appendicitis after receiving the third dose of the Pfizer-BioNTech Coronavirus Disease 2019 (COVID-19) vaccine; no other triggers were identified. We speculate that an association exists which may be mediated by colonic lymphoid hyperplasia, a condition that might be indicative of an enhanced immunological mucosal response to antigenic stimulation. As widespread vaccination coverage continues, it is crucial to monitor and accurately report the adverse reactions that may otherwise remain unidentified in vaccination trials. Therefore, we suggest that adults experiencing spontaneous, severe abdominal pain following COVID-19 vaccination may benefit from seeking emergent medical care. Likewise, providers should have a low threshold to consider and evaluate patients for appendicitis. If a true causal link is identified, the risk must also be deliberated in context with the millions of patients who have been safely vaccinated and the known morbidity and mortality from COVID-19 infection.