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.