Background: Sub-optimal plasma zinc level is hypothesized to initiate prostate carcinogenesis which may indicate a link with PSA levels. Hence, this study was an attempt to verify this link among Nigerian men with prostate cancer (PCa). Methods: This was a prospective cross-sectional study of 220 histologically-verified PCa patients, conducted in a Nigerian third-level health facility. Clinical, demographic and laboratory variables were obtained and analyzed using SPSS version 21. Plasma zinc and total serum PSA were determined using standard methods. Results: High-risk PSA status was observed among the majority (n = 187; 85.0%) of the study cohorts. Most (n = 136; 72.7%) of the cohorts with high-risk PSA status exhibited sub-optimal plasma zinc levels. Inverse relationship existed between plasma zinc and serum PSA among the entire study cohorts (B: -0.401; SE: 2.776; p< 0.001) and among those with high-risk PSA levels (B: -0.309; SE: 2.784; p < 0.001) in unadjusted model. However, the inverse relationship was amplified among the subgroups with high-risk PSA levels (B: -0.322; SE: 0.327; p< 0.001) following adjustment for confounders. Sub-optimal plasma zinc level had greater likelihood of predicting high-risk PSA status in univariate (OR: 2.833; 95% CI: 1.332 – 6.027; p = 0.007) and multivariate (OR: 1.680; 95% CI: 1.157 – 3.937; p = 0.006) logistic regression models than PCa stage, PCa grade, family history of PCa, age, prostate volume, and BMI. Conclusion: The study suggests the association of sub-optimal plasma zinc levels with high-risk PSA status among PCa patients. Optimization of zinc status may, therefore, play a role to mitigate high-risk PCa disease. However, further studies are suggested to evaluate the conclusion of this study.