ImportanceInformation about the trend in illicit substance ingestions among young children during the pandemic is limited.ObjectivesTo assess immediate and sustained changes in overall illicit substance ingestion rates among children younger than 6 years before and during the COVID-19 pandemic and to examine changes by substance type (amphetamines, benzodiazepines, cannabis, cocaine, ethanol, and opioids) while controlling for differing statewide medicinal and recreational cannabis legalization policies.Design, Setting, and ParticipantsRetrospective cross-sectional study using an interrupted time series at 46 tertiary care children’s hospitals within the Pediatric Health Information System (PHIS). Participants were children younger than 6 years who presented to a PHIS hospital for an illicit substance(s) ingestion between January 1, 2017, and December 31, 2021. Data were analyzed in February 2023.ExposureAbsence or presence of the COVID-19 pandemic.Main Outcome(s) and Measure(s)The primary outcome was the monthly rate of encounters for illicit substance ingestions among children younger than 6 years defined by International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnosis code(s) for poisoning by amphetamines, benzodiazepines, cannabis, cocaine, ethanol, and opioids. The secondary outcomes were the monthly rate of encounters for individual substances.ResultsAmong 7659 children presenting with ingestions, the mean (SD) age was 2.2 (1.3) years and 5825 (76.0%) were Medicaid insured/self-pay. There was a 25.6% (95% CI, 13.2%-39.4%) immediate increase in overall ingestions at the onset of the pandemic compared with the prepandemic period, which was attributed to cannabis, opioid, and ethanol ingestions. There was a 1.8% (95% CI, 1.1%-2.4%) sustained monthly relative increase compared with prepandemic trends in overall ingestions which was due to opioids. There was no association between medicinal or recreational cannabis legalization and the rate of cannabis ingestion encounters.Conclusions and RelevanceIn this study of illicit substance ingestions in young children before and during the COVID-19 pandemic, there was an immediate and sustained increase in illicit substance ingestions during the pandemic. Additional studies are needed to contextualize these findings in the setting of pandemic-related stress and to identify interventions to prevent ingestions in face of such stress, such as improved parental mental health and substance treatment services, accessible childcare, and increased substance storage education.