<p>Polysubstance use disorders ( ≥ 2 substance use disorders (SUDs)) are associated with high morbidity and mortality. We analyzed data from 92,233 adult participants in the 2022–2023 US National Surveys on Drug Use and Health to estimate past-year prevalence of polysubstance use disorders and to examine their associations with age of substance use initiation. Multivariable logistic regression and Poisson regression were applied. Age- and sex-adjusted past-year prevalence of 2 SUDs was 19.2–44.9% (95% CIs=11.1–62.3%) among adults with any SUD. Age- and sex-adjusted past-year prevalence of ≥3 SUDs ranged from 16.4% (95% CI = 14.3–18.6%) among adults with cannabis use disorder, to 32.4–44.7% (95% CIs=29.1–51.3%) among those with opioid use disorder or prescription stimulant or tranquilizer/sedative use disorder, and up to 48.2–72.0% (95% CIs=39.4–81.7%) among those with methamphetamine, cocaine, or hallucinogen use disorder. Overall, compared to adults who initiated substance use before age 18, the number of SUDs was 73–83% lower for those who initiated at age ≥21 (range of incidence density ratios (IDRs)=0.17–0.27, 95% CIs=0.12–0.31). Specifically, compared with corresponding adult counterparts who initiated before age 18, the number of moderate-severe SUDs was 32% lower among those initiating alcohol at ages 21–29 (IDR = 0.68, 95% CI = 0.57–0.83), 21% lower among those initiating cannabis at ages 21–29 (IDR = 0.79, 95% CI = 0.69–0.90), and 45–62% lower (IDRs=0.38–0.55, 95% CIs=0.31–0.76) among adults who never initiated alcohol, cannabis, or nicotine use. The elevated prevalence of polysubstance use disorders associated with early initiation of substance use underscores the critical need for evidence-based strategies to prevent alcohol, cannabis, and nicotine consumption before age 21.</p>