Aim: To investigate how a nationwide lockdown influences the incidence of appendicitis. Background: Communitive infectious diseases may play a role in the pathogenesis of appendicitis as indicated by a seasonal variation in the incidence rate. The spread of communitive infectious diseases has decreased during the COVID-19 pandemic lockdown; thus, we have an opportunity to study the incidence rate of appendicitis in an environment with less impact from common community infections. Methods: The study is a nationwide register-based cohort study of the entire Danish population of 5.8 million. The difference in the incidence of appendicitis in a population subjugated to a controlled lockdown with social distancing (study group) was compared to a population not subjugated to a controlled lockdown and social distancing (reference group). Results: The relative risk of appendicitis during the lockdown was 0.92 (95% confidence interval (CI): 0.82–1.03, p = 0.131). The relative risk of complicated appendicitis during the lockdown was 0.68 (95% CI: 0.49–0.93, p = 0.02). The incidence of uncomplicated appendicitis was not significantly different during the national lockdown. Conclusions: During the national lockdown of Denmark due to the COVID-19 pandemic the incidence of complicated appendicitis was reduced significantly compared to previous years, indicating that infectious disease might be a factor in the pathogenesis of appendicitis with complications. Trial Registration: The study was registered on ClinicalTrials.gov (NCT04407117).