Background: Prostate-specific antigen (PSA) is influenced by abnormalities commonly seen in type 2 diabetes, yet evidence from African populations remains limited. Understanding how PSA relates to cardio-metabolic biomarkers in Nigerian men may improve prostate health assessment in settings with increasing rates of diabetes and obesity. Objectives: This study compared PSA concentrations and cardio-metabolic biomarkers between men with type 2 diabetes and non-diabetic controls, examined age-related variation, and assessed associations involving body mass index, lipid profile, blood pressure, and duration of diabetes. Methods: A case-control study was conducted among 86 diabetic men and 60 non-diabetic controls attending two tertiary hospitals in Nigeria. Anthropometric indices and blood pressure were measured. Fasting glucose, total PSA, free PSA, and lipid fractions were analysed using standard biochemical assays. Statistical analyses included t tests, chi-square tests, one-way analysis of variance, Spearman correlation, and multivariable linear regression to adjust for confounding. Results: Diabetic men represented 58.9% of the sample and were significantly older than controls, reflecting the pattern of clinic attendance during the recruitment period (p < 0.001). Total PSA did not differ significantly between diabetic and non-diabetic participants (t = 1.65, p = 0.10), whereas free PSA was higher among diabetic men (t = 2.19, p = 0.03). Diabetic men had significantly higher BMI (t = 4.49, p < 0.001), fasting glucose (t = 2.70, p < 0.01), systolic blood pressure (t = 3.81, p < 0.001), and diastolic blood pressure (t = 5.88, p < 0.001). Significant differences were also found for total cholesterol (p = 0.03), HDL cholesterol (p < 0.001), and LDL cholesterol (p < 0.01). In adjusted analyses, diabetes status was not independently associated with total PSA, whereas age remained an important predictor of PSA variation. The association between diabetes status and free PSA was attenuated after adjustment. Duration of diabetes was not associated with PSA or glucose. Conclusion: PSA interpretation in Nigerian men should take account of age, adiposity, and broader cardio-metabolic status. The observed difference in free PSA warrants further investigation but should be interpreted cautiously. These findings highlight the importance of considering metabolic context when evaluating prostate health in men with diabetes.