In the United States, the novel compound duloxetine has been approved for the treatment of major depressive disorder (MDD) and diabetic peripheral neuropathic pain in the adult population. There are currently no published data on the use of duloxetine in children and adolescents. This report describes the successful treatment of 2 adolescent females with chronic pain and co-morbid MDD. Both patients required admission to a tertiary-care pediatric hospital due to the chronicity, severity, and treatment resistance of their pain syndromes. In both cases, duloxetine provided rapid improvement in the experience of pain, as well as mood symptoms, at minimum dosages. Pain symptom reduction and restoration of a euthymic state was maintained at 4- and 3-month follow-up visits, respectively, with minimal to no adverse effects being reported. These cases present preliminary evidence of promising uses for duloxetine in the pediatric population.