An analysis of final 2021 DAWN data presents: (1) nationally representative weighted estimates, including percent and unadjusted rates per 100,000, for all drug-related emergency department (ED) visits, (2) nationally representative weighted estimates for the top five drugs in drug-related ED visits, (3) the assessment of monthly trends and drugs involved in polysubstance ED visits in a subset of sentinel hospitals, and (4) the identification of drugs new to DAWN’s Drug Reference Vocabulary.