PSA, abbreviated of “Prostate-Specific Antigen” is widely used as a considered a significant cancer biomarker for diagnosing prostate cancer. Improvement of a fast, facile, and less cost with high accurate/sensitive/selective methodologies for the PSA determination is stock-still a challenge. In this work, we reported a simple biosensor based on a Zn(II) metal-organic framework nanoparticles (Zn-MOF-NPs) derived from reaction of zinc acetate with nano organic linker. The structure, morphology, and physicochemical properties of the prepared Zn(II)-MOF-NPs were definite using various spectroscopic and microanalytical tools as SEM-EDX, HR-TEM, XRD, XPS, elemental analysis, FT-IR, UV-vis spectroscopy, mass spectroscopy, thermogravimetric Analysis (DSC/TGA), and photoluminescence (PL). Obviously, the results revealed that the Zn(II)-MOF-NPs is chemical stable, highly selective and sensitive to PSA, without interferences with other common interfering analytes. The detection limit for PSA was 0.145 fg/mL, in a wide-linear range of concentrations (0.1 fg/mL-20 pg/mL), with a correlation coefficient 0.983. The Zn(II)-MOF-NPs was successfully used as an up-and-coming biosensor for PSA-monitoring and quantification in biological real samples (plasma/whole blood/serum) at clinical target concentration levels. Moreover, the present approach will help the human-beings from the hazard’s prostatic cancer through early discovery and diagnosis process via the detection of PSA at low limits of concentrations. Meantime, the interaction mechanism between the Zn(II)-MOF-NPs and PSA was well studied and investigated.