Mean platelet volume (MPV) is an indicator of platelet activation and has been proposed as a diagnostic marker for several kinds of cancers. We investigated the value of MPV as a diagnostic marker for prostate cancer (PCa) and examined whether MPV in combination with prostate-specific antigen (PSA) could increase the sensitivity or specificity of PSA for PCa diagnosis. For this study, 107 pathologically confirmed PCa and 177 non-PCa patients who underwent prostate biopsy were retrospectively studied. Clinical data and pre-biopsy hematological parameters were collected. The above parameters were compared between PCa and non-PCa patients. The correlation between MPV and clinical characteristics was analyzed. Receiver operating characteristic (ROC) analysis was used to explore the diagnostic value of MPV for PCa. Among all parameters analyzed, the difference was only found in MPV, platelet distribution width (PDW), and PSA between PCa and non-PCa patients. MPV was significantly decreased and PDW increased in PCa than that of non-PCa among men. ROC analysis identified MPV ≤ 9.05 fl as a cut-off value for potential PCa with area under the ROC curve (AUC) = 0.783, 95% CI = 0.733–0.833, sensitivity = 0.746, and specificity = 0.708. AUC and the sensitivity of MPV were comparable with total PSA (TPSA) or free PSA (FPSA). However, the specificity of MPV was larger than that of TPSA (0.461) or FPSA (0.561). Furthermore, MPV combined with TPSA or FPSA further enhanced the specificity of TPSA (0.844) or FPSA (0.927), but PDW did not. These findings suggested that MPV could have a predictive value for the diagnosis of PCa. MPV in combination with TPSA or FPSA could enhance the specificity of PSA and may reduce the rate of unnecessary biopsy for patients with high levels of PSA.