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This study evaluated the feasibility, acceptance, and potential clinical benefit of brief applied behavior analysis (ABA)-based interventions for children and adolescents with autism spectrum disorder (ASD) displaying challenging behaviors during hospitalizations. Participants included 36 children diagnosed with ASD, 6-17 years of age, who were medically or psychiatrically hospitalized. Children in the intervention group received a brief ABA intervention and were compared to children in the evaluation and monitoring-only group. Families and staff recommended the intervention, children receiving the intervention demonstrated significantly more improvement in unblinded ratings of clinical severity, data from physicians indicated a positive effect of the intervention on levels of staffing and restraints and attending medical providers universally reported satisfaction and benefit of the intervention. Improvements in challenging behaviors were not significantly different as reported by parents, and the length of hospitalization did not differ between the groups. Ultimately, the outcomes of this pilot study suggest incorporating specialized ABA-based assessment and intervention during hospitalization may be feasible and well accepted by clinicians and families. However, future research must address potent methodological challenges related to capturing meaningful data during hospitalizations in order to answer questions of ultimate pragmatic, clinical, and system-level benefits. Trial Registration ClinicalTrials.gov Identifier NCT02339935, Registered 16 January 2015, First participant consented 23 February 2015. Autism Res 2020, 13: 1072-1078. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Inpatient hospitalizations for children with autism spectrum disorder (ASD) and severe behavior are common, challenging, and costly in terms of human experience. This study evaluated the benefit of brief applied behavior analysis-based interventions to children and adolescents with ASD displaying challenging behaviors during hospitalizations. Families and staff evaluating the procedures noted perceived potential benefits of the intervention, but this initial pilot study did not document changes in hospitalization length or blinded rating of improvement., (© 2020 International Society for Autism Research, Wiley Periodicals, Inc.)