Lead (Pb) ion detection poses a critical problem, particularly in environmental monitoring, industrial operations, and public health, especially for young children and expecting women. Determining lead levels in blood early on is essential to minimizing the long-term consequences of lead exposure. Several sophisticated detection instruments, such as mass spectrometers which perform with high sensitivity, specificity and accuracy, but require a lab-based setting, multi-step sample preparation, expensive payment and professional operation. It is evident that a highly sensitive, portable, low-cost, quick sample-to-result, blood lead detection device that can be tested at the point-of-care is necessary. Consequently, we developed a unique ZnO/PEDOT:PSS nanocomposite layer integrated with a CMOS MEMS-based bridge-like membrane-type (BM) nanomechanical sensor for detecting lead levels in blood. PEDOT:PSS was combined with ZnO nanorods to increase lead ion binding. The sensor responds seven times better to lead ions using nanorods in the detecting layer. A linear resistance change rate response was found from 0.005 to 10 ppm, with the limit of detection (LOD) of 0.12 ppb. Similarly, our BM nanomechanical sensor can correctly assess Pb2+ in human serum with recovery rates of 86.25–150 %. Measurements of human blood samples from patients with varying lead ion concentrations validated by the standard AAS show a good linear connection with the BM nanomechanical sensors' concentration, with a regression coefficient of 0.92. This describes the first micromachined nanoachanical sensing system for detection of Pb2+ in only 5 μL of human serum sample. The device achieves a time-to-result of less than 10 min. The system is designed to be very sensitive and offers affordable, disposable sensing chips together with a portable signal acquisition platform.