Post-marketing pharmacovigilance is essential because not all adverse drug reactions can be identified before approval. The Korea Institute of Drug Safety and Risk Management (KIDS) monitors spontaneous adverse event reports collected through the Korea Adverse Event Reporting System (KAERS). This study evaluated the contribution of signal accumulation and reassessment to regulatory actions. Serious adverse event reports submitted between 2016 and 2020 were reviewed using individual case assessment, qualitative assessment of Designated Medical Events, and quantitative data mining. Among 8,528 drug–serious adverse event combinations evaluated, 2,691 included at least one case for which causality could not be excluded. Further evaluation identified 241 combinations not reflected in Korean drug labeling, of which 131 underwent reassessment based on accumulated evidence. Twenty-one were ultimately determined to be meaningful safety signals and led to proposals to the Ministry of Food and Drug Safety, followed by Korean labeling changes. These findings highlight the value of systematic signal accumulation and reassessment in identifying safety issues that may not initially warrant regulatory action and in supporting post-marketing regulatory decision-making.