OBJECTIVE: To quantify the annual direct healthcare cost of intentional overdose and other types of self-harm resulting in emergency department (ED) and/or inpatient encounters among youth in the United States (U.S.). METHODS: Using the 2021 Nationwide Emergency Department Sample (NEDS) and National Inpatient Sample (NIS) datasets, produced by the Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP), we determined nationally representative cross-sectional frequencies and costs for specific types of self-harm encounters among 8- to 21-year-old pediatric and young adult patients. RESULTS: The total combined one-year cost of all self-harm encounters was 69 million (95% CI 41M-97M). The majority of this cost was due to intentional overdose-related encounters, which totaled 30 million (95% CI 12M-47M). Of this total, 32 million (95% CI 23M-41M) was paid by public insurers and 96 million (95% CI 81M-12M) was paid by private insurers. Encounters by females accounted for 79% of the intentional overdose costs (20 million, 95% CI 04M-35M). CONCLUSION: Based on 2021 data, preventing youth intentional overdose could save the U.S. health system up to 30 million, annually. As we collectively work to prevent suicide deaths among young people, it is important to recognize the needs of the larger group of youth who are engaging in serious self-harm and non-fatal suicidal acts, the majority of whom are young females. Prevention of intentional overdose in this population should be a priority, both in terms of upstream public health efforts and promotion of evidence-based methods of safer storage.