Pediatric and young adult patients frequently present to medical inpatient (MIP) units for treatment of substance use disorder (SUD). Given the risk of lifelong dependence and related complications in early life substance use (SU), a review of the literature is warranted. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) systematic review of literature published through April, 62,020, which examined incidence, screening, and complications of pediatric and young adult SU in the MIP setting. 8843 articles were screened, and 28 articles were included for final qualitative synthesis. The overall prevalence of SU-related discharge diagnoses ranged from 1.3% to 5% for patients aged 0 to 26 years. When compared to adult patients, nearly double the rate of co-morbid psychopathology was observed. Three studies utilized systematic screening tools, with the remainder relying on biologic screens and admission or discharge diagnoses. The results of our review indicate that current screening practices for SU in the MIP clinical setting are subpar and likely result in an underestimation of incidence and morbidity due to limited use of systematic screening tools. Despite this, incidence of SU hospitalizations and related medical and psychiatric complications continue to rise.