Objective The purpose of this systematic review was to synthesize quantitative or mixed-method studies that evaluate the efficacy of interventions with youth in the context of psychiatric residential treatment facilities (PRTFs) in the United States. Methods Systematic review procedures were conducted to identify relevant studies, both published and from the gray literature in the United States. Search terms were informed via consultation with a university social science reference librarian, and four electronic databases were searched. Using a priori inclusion and exclusion criteria, team-based search procedures yielded a final sample of 47 relevant studies. Results Studies varied with respect to publication status; sample size; research design; youth gender identity; youth racial/ethnic identity; youth behavioral, psychological, and developmental or intellectual concerns at intake; outcomes measures; and interventions evaluated. Evaluated interventions could be clustered into one of five categories: (a) modifications to system of treatment, (b) therapeutic modalities, (c) educational/alternative programs, (d) practice behaviors, and (e) post-discharge engagement. The majority of studies noted youth outcome improvements; however, some studies also yielded mixed, inconclusive, or null results. Conclusions We would characterize the breadth and depth of research in this area to be insufficient in providing PRTF stakeholders a clear and firm understanding of “what works” for youth. Thus, one major implication of our review is the need for more research and efforts to incentivize the evaluation of ongoing practices in youth PRTFs. Still, this systematic review can serve as a convenient reference that can inform tentatively PRTF stakeholders’ decisions about the selection of interventions or practice behaviors