Background: Disability and impaired health-related quality of life can persist for months among injured children. Previous studies of long-term outcomes have focused mainly on children with specific injury types rather than those with multiple injured body regions. This study's objective was to determine the long-term functional status and health-related quality of life after serious pediatric injury, and to evaluate the associations of these outcomes with features available at hospital discharge. Study Design: We conducted a prospective observational study at 7 Level I pediatric trauma centers of children treated for at least 1 serious (Abbreviated Injury Scale severity 3 or higher) injury. Patients were sampled to increase the representation of less frequently injured body regions and multiple injured body regions. Six-month functional status was measured using the Functional Status Scale (FSS) and health-related quality of life using the Pediatric Quality of Life Inventory. Results: Among 323 injured children with complete discharge and follow-up assessments, 6-month FSS score was abnormal in 33 patients (10.2%)—16 with persistent impairments and 17 previously normal at discharge. Increasing levels of impaired discharge FSS score were associated with impaired FSS and lower Pediatric Quality of Life Inventory scores at 6-month follow-up. Additional factors on multivariable analysis associated with 6-month FSS impairment included older age, penetrating injury type, severe head injuries, and spine injuries, and included older age for lower 6-month Pediatric Quality of Life Inventory scores. Conclusions: Older age and discharge functional status are associated with long-term impairment of functional status and health-related quality of life. Although most seriously injured children return to normal, ongoing disability and reduced health-related quality of life remained 6 months after injury. Our findings support long-term assessments as standard practice for evaluating the health impacts of serious pediatric injury.