Acetaminophen is a commonly used analgesic and antipyretic that has become more accessible in the Republic of Korea after a 2012 policy change that permitted over-the-counter (OTC) sales in convenience stores. Although effective when used correctly, its increased availability raises concerns about misuse and self-harm, particularly among adolescents. Therefore, this study investigated the effects of this policy shift on the rate of acetaminophen poisoning in adolescents in the Republic of Korea. National health data was analyzed to assess the trends in acetaminophen poisoning among adolescents before and after the 2012 policy change. This analysis included the demographic and clinical characteristics of the poisoning cases and compared the rates across different age groups, income levels, and time periods. The analysis revealed an increase in acetaminophen-related self-poisoning incidents following policy changes. Specifically, an increase in the number of cases per 100,000 individuals per patient was observed, thereby indicating frequent and recurrent poisoning. Furthermore, the total number of cases increased, whereas the number of patients remained stable, suggesting that individual cases of repeated poisoning have become more common. Notably, the increase in adolescents aged 16–18 years was more pronounced than that in adolescents aged 13–15 years. Additionally, the proportion of acetaminophen poisoning cases relative to the total number of drug poisoning cases increased. However, the rate of severe acetaminophen poisoning requiring hospitalization remained unchanged. These findings indicate a potential association between the increased availability of acetaminophen and an increase in self-poisoning cases among adolescents, particularly in older age groups. This underscores the urgent need for targeted public health interventions, including stricter regulatory measures for OTC sales and enhanced educational programs to prevent misuse and protect vulnerable populations.