The present invention provides a lead-on detection circuitry of a biopotential acquisition system. The lead-on detection circuitry includes an input terminal, a duty-cycle controller, a transmitting signal generator and a mixer-based receiver. The duty-cycle controller is configured to generate a first clock signal. The transmitting signal generator is configured to generate a transmitting signal to the input terminal according to the first clock signal. The mixer-based receiver is configured to perform a mixing operation based on the first clock signal and the transmitting signal to generate an output signal, wherein the output signal indicates if an electrode of the biopotential acquisition system is in contact with a human body, and the electrode is coupled to the input terminal.