The combination of opioid misuse and cigarette smoking contributes to increased morbidity and mortality compared to each substance use alone. We estimated the incidence of opioid misuse for persons who currently or formerly smoked versus never smoked. Data came from the 2015-2020 National Surveys on Drug Use and Health cross-sectional surveys of US civilians aged 12+ (n = 315,661). Weighted opioid misuse incidence and average time between cigarette use initiation and opioid misuse initiation were calculated annually by smoking status. Logistic regression models tested time trends in incidence by smoking status. Overall, 0.75% of persons initiated opioid misuse per year; opioid misuse incidence was 1.35% for those who currently smoked cigarettes, 0.54% for those who formerly smoked, and 0.67% for those who never smoked. For persons who currently smoked and misused opioids (1.50%), 95.08% smoked prior to opioid use. The average time between smoking followed by opioid misuse was 12.93 years and for opioid misuse followed by smoking was 4.36 years. Persons who currently smoked were more likely to initiate opioid misuse than those who had never smoked (AOR = 1.81, 95% CI: 1.60, 2.06). There was a decrease in the opioid misuse incidence over time (AOR = 0.90; 95% CI: 0.85, 0.92), which did not differ by smoking status. Persons who currently smoked cigarettes, relative to those who never smoked, were more likely to initiate opioid misuse. As most individuals smoked before opioid misuse, it may be useful for primary prevention efforts to decrease opioid misuse initiation by focusing on smoking status.