The relationships among depression, anxiety, and quality of life were tested, as were the effects of age, gender, and pain frequency on these variables in children (n = 44) and adolescents (n = 31) with sickle cell disease. Participants completed the Revised Child Anxiety and Depression Scale (RCADS) and the Pediatric Quality of Life (PedQL Generic Model). The mean and standard deviation for summary RCADS scores for the majority of participants were below the clinical thresholds of T < 65, indicating low risk for depression (n = 65; 89.3%) and anxiety (n = 70; 93.3%). The subscale scores for the different dimensions of QOL health were a) psychosocial (73.3 ± 15.9), b) emotional (75.0 ± 20.7), c) social (80.8 ±19.1), d) school functioning (64.0 ≥ 19.8), and e) physical (77.4 ± 17.4). Significant negative correlations were found between mean total quality of life scores and symptoms of a) general anxiety (r = -0.51, p < 0.0001), b) depression (r = -0.66, p < 0.0001), c) obsessive compulsive (r = -0.53, p < 0.0001), d) panic (r = -0.60, p < 0.0001), and e) social phobia (r = -0.57, p < 0.0001). Age and gender did not have significant effects on risk for depression and anxiety or poor QOL. Pain frequency also did not have significant effects on the risk for depression and anxiety. Findings suggest that health care providers need to screen for anxiety and depression, and make referrals for early interventions to improve quality of life and promote school function in youth with sickle cell disease.