Youth with sickle cell disease (SCD) experience frequent pain, which is related to their functioning and health-related quality of life (HRQoL). A growing body of literature suggests that rather than the experience of pain experience itself, the cognitive appraisal of pain is critical. The overall aim of the current study was to examine the relationship between child pain catastrophizing, parent response to child pain symptoms, and health-related outcomes (i.e., functional disability, health-related quality of life; HRQoL). Results indicated that pain catastrophizing significantly predicted functional disability and HRQoL above and beyond children’s experience of pain. Additionally, protective, minimizing, and encouragement/monitoring parent responses each moderated the relationship between pain catastrophizing and HRQoL; for youth who engaged in moderate to high levels of pain catastrophizing, parent response to pain appeared to be more impactful on HRQoL. Clinical implications regarding intervention for pain catastrophizing and parent response to pain are discussed.