Background <p>Acetaminophen is a commonly used analgesic and antipyretic. In South Korea, a 2012 regulatory change allowed its over-the-counter sale in convenience stores, increasing public accessibility.</p> Objectives <p>We aimed to assess the impact of increased over-the-counter availability of acetaminophen on adolescent self-poisoning trends in South Korea.</p> Methods <p>This population-based observational study used the National Health Insurance Service customized database to analyze trends in acetaminophen-related poisoning among adolescents before and after the 2012 policy change. Age-specific trends were evaluated, and poisoning episodes were categorized by recurrence and severity.</p> Results <p>Following the policy change, the number of acetaminophen poisoning cases increased from 2.4 to 3.8 (during 2007–11 and 2013–17, respectively, per 100,000 adolescents). This increase was particularly significant among adolescents aged 16–18 years, rising from 10.7 to 23.8 per 100,000 (<i>p</i> &lt; 0.05). While the total number of poisoning events increased, the number of affected individuals remained largely unchanged (86.4 vs 80.0), suggesting a more frequent recurrence. The proportion of acetaminophen poisonings among all drug poisoning cases increased from 5.2% to 9.7%, whereas the increase in the proportion of severe cases requiring hospitalization was relatively modest.</p> Conclusions <p>The findings suggest that increased over-the-counter availability of acetaminophen may be associated with a rise in misuse among older adolescents. Public health measures, including stricter over-the-counter regulation and targeted interventions, may be needed to mitigate the risk of self-harm in this population.</p>