To evaluate the feasibility, reliability, validity, and responsiveness of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL) in the first 2 weeks after pediatric emergency department care of minor injury. Prospective cohort study. Pediatric hospital emergency department. Children and adolescents with minor injury (n=334). Child- and parent-reported clinical outcomes and PedsQL scale scores. The PedsQL had good to excellent internal consistency reliability (α range, 0.73-0.93). For each day that the clinical symptoms persisted, there were consistent decreases in mean health-related quality of life (HRQOL) scores (validity testing). There were significantly greater negative changes in mean HRQOL scores for fractures vs soft-tissue injuries and for lower vs upper extremity injuries. Clinical outcomes categorized as poor had large negative changes in HRQOL not seen in good outcome groups. Distribution-based indicators of change supported good responsiveness (effect sizes for the physical summary score, 0.01-2.44; group differences at follow-up exceeded estimates of the minimal importance difference). The PedsQL is feasible, reliable, and demonstrates good construct and discriminant validity and responsiveness in measuring short-term outcome after minor injury care in the pediatric emergency department. Assessing short-term outcome from the patient perspective with HRQOL measures may greatly enhance our ability to evaluate the effectiveness of emergency department care.