The objective of this study was to examine the associations between spirituality and overall quality of life (QOL) and individual QOL domains in black patients with cancer pain. A secondary data analysis of a parent study exploring pain medication adherence in black patients receiving around-the-clock opioids with cancer pain was performed. All the participating patients completed Functional Assessment of Chronic Illness Therapy—Spiritual Well-Being Scale (spirituality), Brief Pain Inventory (pain severity and interference), Edmonton Symptom Assessment Scale (symptoms), and Functional Assessment of Cancer Therapy—General (QOL). Pearson correlation and multiple linear regression analyses were conducted to examine the associations between spirituality and overall QOL and QOL domains and to identify the predictors of overall QOL and QOL domains. Black patients treated for cancer pain (n = 102) completed the study. Pearson correlation showed significant positive associations between spirituality and overall QOL (P < 0.001) and individual QOL domains (physical, social, emotional, and functional). Higher spirituality was associated with lower pain severity (P = 0.01), pain interference (P = 0.001), and total symptoms score (P < 0.001). In multiple regression analysis, the best model for the overall QOL explained 67% of the variance (P < 0.001) and included total symptoms score, pain interference, spirituality, and age. Spirituality significantly predicted QOL domains of social (P < 0.0001), emotional (P = 0.002), and functional well-being (P = 0.001) rather than physical well-being. Spirituality is associated with decreased pain and lower symptom burden and may serve as a protective factor against diminished overall QOL, specifically social, emotional, and functional domains in black patients with cancer pain. There is a need to develop spirituality-based interventions along with symptom management interventions to improve QOL for this population.