Appendicitis is one of the most common abdominal surgical emergencies worldwide; however, its causes remain poorly understood. The Japanese Adverse Drug Event Report (JADER) database is a spontaneous reporting system (SRS) that can be utilized to analyze the safety signals of adverse events. In this study, we investigated the association between drug use and the onset of appendicitis using the JADER database. We first used the reporting odds ratio (ROR) as the signal and found signals for appendicitis, perforated appendicitis, and complicated appendicitis for 23, 9, and 1 drug, respectively. To investigate the level of hazard over time in drug-associated appendicitis, the Weibull shape parameter β was calculated using a Weibull plot, which revealed drug-dependent patterns for changes in the risk of appendicitis over time for the eight drugs. Furthermore, logistic regression analysis was performed to account for the influence of age, sex, and primary disease, and a significant association was detected between two drugs and appendicitis. Several types of drugs, such as antitumor, antirheumatic, and anti-inflammatory drugs, were included in our analyses; however, only clozapine, which is used for patients with schizophrenia, was commonly identified in these analyses. The resulting data suggest that certain drugs may be associated with appendicitis and may require adequate attention.