Poor understanding of the clinicopathological features of prostate cancer (CaP) in Black men (BM) is one of the major challenges implicated in the management and prevention of the disease. The development of CaP involves an accumulation of multiple oncogenic events with associated increase in prostate specific antigen (PSA) and stress related hormones such as Cortisol. This data aim to examine the role of Cortisol and health-related quality of life (HRQoL) in CaP development. Data was collected as part of a large CaPTC Familial CaP Cohort Study. The HRQoL indicators were measured and salivary Cortisol levels evaluated by enzyme immunoassay. CaP tissue expression patterns of cortisol and Annexin V were also studied by immunohistochemistry. The HRQoL indicators showed a significant difference between participants with and without physical activity (P = 0.025), stress (P = 0.008) and self-care (P = 0.005). There was significant increase in salivary cortisol levels in the CaP patients compared to CaP-free participants (P = 0.003). The salivary cortisol level for the CaP patients ranged from 1.029 µg/dL to 0.037 µg/dL while the range for the CaP-free participants was from 0.139 µg/dL to 0.026 µg/dL. In addition, we found increased expression of the cortisol protein in CaP patients with Gleason score 8 compared to those with lower scores and the CaP tissues showed overexpression of Annexin V protein. Salivary and tissue cortisol levels with an accompanying Annexin V expression may serve as important biomarkers for prostate cancer diagnosis and prognosis in West African Black men.