Substance use disorders (SUDs) are characterized by impairment caused by the recurrent use of alcohol, illicit drugs, or both. SUDs are pervasive and endemic among US adolescents, with potentially negative health and social consequences. Although the term experimentation normalizes adolescent substance abuse, the long-term consequences of this behavior beginning in adolescence can be detrimental to not only the adolescent but also the adult into which he or she develops. Our objective was to examine the epidemiology of SUD among hospitalized US adolescents, 13 to 19 years of age, during the time period 2000-2019. A case-control study was conducted using 5,260,104 hospital discharge records (394,952 SUD and 4,865,152 non-SUD) from the 2000-2019 Kids' Inpatient Database. SUD and clinical outcomes variables were identified based on the International Classification of Diseases, Ninth/Tenth Revisions, Clinical Modification, coding. SUD rates (per 1000 discharges) were calculated and adjusted odds ratios (aORs) with their 95% confidence intervals (CIs) were computed using logistic regression models for predictors of SUDs among hospitalized adolescents. The prevalence of SUDs was estimated to be 75.10 cases per 1000 discharges (95% CI 74.86-75.31). Demographically, the highest crude rates (per 1000 discharges) were seen among Native American (139.58) and White (91.97) patients. Adolescent patients who experienced SUD were twice as likely as nonusers to be 16 to 19 years of age (aOR 2.2, 95% CI 2.13-2.19) or to be male (aOR 2.2, 95% CI 2.22-2.27). SUD was significantly associated with cooccurring conditions, including anxiety (aOR 2.5, 95% CI 2.48-2.53), depression (aOR 2.3, 95% CI 2.30-2.35), mood disorder (aOR 2.17, 95% CI 2.14-2.20), schizophrenia (aOR 2.6, 95% CI 2.52-2.64), sexually transmitted infections (aOR 2.3, 95% CI 2.23-2.45), hepatitis (aOR 3.0, 95% CI 2.87-3.15), and suicide (aOR 1.33, 95% CI 1.30-1.35). The study examined the epidemiology, risk factors, and common characteristics of hospitalized adolescent patients with SUDs. The high burden of psychiatric and medical comorbidities observed among this patient group warrants designing effective and comprehensive substance use prevention and treatment programs for youths.