ABSTRACT: The U.S. drug overdose epidemic continues to cause substantial morbidity and mortality. In 2017, 967,615 nonfatal drug overdoses were treated in emergency departments (EDs), a 4.3% increase from 2016 in all overdoses and a 3.1% increase in opioid-involved overdoses (1). During 2017 and 2018, syndromic surveillance revealed that 37.2% of overdoses treated in EDs in 18 states involved multiple drugs (2). To describe changes in rates and proportions of suspected nonfatal drug and polydrug overdoses treated in EDs, CDC analyzed syndromic surveillance data from 2018 to 2019 in 29 states. Rates of overdoses involving opioids, cocaine, and amphetamines increased 9.7%, 11.0%, and 18.3%, respectively, and the rate of benzodiazepine-involved overdoses decreased 3.0%. Overdoses co-involving opioids and amphetamines increased from 2018 to 2019, overall, in both sexes, and in most age groups. In 2019, 23.6%, 17.1%, and 18.7% of overdoses involving cocaine, amphetamine, and benzodiazepines, respectively, also involved opioids. Expanding overdose prevention, treatment, and response efforts is needed to reduce the number of drug and polydrug overdoses. This includes linkage into treatment, harm reduction services, and community-based programs for persons who use drugs; expanding overdose prevention efforts, including increased naloxone provision, to persons who use stimulants; addressing the illicit drug supply; and identifying specific risk factors for populations using these drugs. Continued surveillance with expanded coverage of additional jurisdictions of the evolving drug overdose epidemic is important to the success of these efforts.