We present the case of a 15-year-old adolescent boy with a neurobehavioral disorder who experienced a brain injury during the first month of life. The forms of challenging behaviors were severe and included aggression, property destruction, volitional incontinence, and suicidal statements, and had resulted in two psychiatric hospitalizations and multiple emergency evaluations prior to intervention. The intervention was preceded by a functional behavior assessment suggesting that a differential reinforcement intervention could be designed to minimize reinforcement of challenging behaviors while maximizing reinforcement of adaptive, positive behaviors. The intervention was introduced following the baseline phase and there was an immediate decrease in the rate of challenging behaviors and in the utilization of emergency psychiatric services. Improvements continued for 6 weeks, after which a medication was added to promote sleep onset (to decrease sleep onset latency) along with behavioral guidelines, which led to further improvements for an additional 12 weeks. A follow-up phase of 3 months showed sustained results. The study illustrates the value of an integrated approach utilizing applied behavior analysis and sequenced neuropsychiatry, and a neurobehavioral formulation where components of the participant’s brain injury history are integrated with an operant formulation as circumstances that explain the problem behavior while effectively suggesting strategies for behavioral treatment. Because the intervention was implemented by support staff in a group home, it illustrates the ability of support staff to work therapeutically with severe behavior presentations using structured behavioral interventions.