Adults with sickle cell disease (SCD) often have chronic pain, screen positive for depressive symptoms more frequently than the general population, and have higher levels of pain catastrophizing than other chronic non-cancer pain patients. Both depressive symptoms and pain catastrophizing may exacerbate pain severity and interference. This study examined whether pain catastrophizing mediates the relationship between depressive symptoms and pain outcomes in adults with SCD and chronic pain, using baseline data from the GRACE Trial, a randomized controlled hybrid effectiveness-implementation study. Recruited from five U.S. healthcare systems, 330 participants provided data for this analysis. Depressive symptoms (Patient Health Questionnaire-9 [PHQ-9]), pain catastrophizing (Pain Catastrophizing Scale [PCS]), pain intensity/interference (Pain, Enjoyment of Life, and General Activity [PEG]), and pain impact (Pain Impact Score [PIS]) were assessed. Path analysis evaluated mediation effects. Results showed that 40% of participants reported moderate to severe depressive symptoms. The mean PCS score (21.3 ± 12.8) indicated clinically relevant catastrophizing. Mean scores for the PEG (6.1 ± 2.0) and PIS (30.3 ± 7.9) also indicated clinically relevant pain interference and impact. Depressive symptoms were moderately correlated with PCS, PEG, and PIS. Pain catastrophizing partially mediated the relationship between depressive symptoms and PIS (indirect effect β = 0.095, p = .011), with significant direct effects persisting (PIS: β = 0.299, p < .001); findings were similar for the PEG outcome. Findings suggest that depressive symptoms are associated with worse pain outcomes directly and indirectly through catastrophizing, highlighting the need for integrated interventions targeting both depression and cognitive-affective pain responses in SCD to improve pain management. Clinical trial registration NCT04906447.