Objectives. To understand important changes in co-occurring opioid and nonopioid drug use (i.e., polysubstance use) within the opioid epidemic in the United States. Methods. We analyzed survey data on the past month co-use of prescription and illicit opioids and 12 nonopioid psychoactive drug classes from a national sample of 15 741 persons entering treatment of opioid use disorder. Results. Past-month illicit opioid use increased from 44.8% in 2011 to 70.1% in 2018, while the use of prescription opioids alone dropped from 55.2% to 29.9%, yet overall remained high (94.5% to 85.2%). Past-month use of at least 1 nonopioid drug occurred in nearly all participants (> 90%), with significant increases in methamphetamine (+85%) and decreases across nonopioid prescription drug classes (range: -40% to -68%). Conclusions. Viewing opioid trends in a “silo” ignores the fact not only that polysubstance use is ubiquitous among those with opioid use disorder but also that significant changes in polysubstance use should be monitored alongside opioid trends. Public Health Implications. Treatment, prevention, and policymaking must address not only the supply and demand of a singular drug class but also the global nature of substance use overall.