The present invention relates to an LED driving circuit and a serial LED illumination system. The LED driving circuit compares a data signal with a voltage threshold via a comparator to output a mode selection signal. The register unit includes an instruction register and a data register. The register unit is coupled to the comparator unit and controlled by the mode selection signal to perform an instruction or data transmission mode. The instruction register stores the instruction data under the instruction mode. The data register stores the illumination display data under the data transmission mode. When the data register is full, the register unit outputs a secondary data signal. The driving unit is controlled by the instruction data and drives an LED module according to the illumination display data. The serial LED illumination system includes a controller that is connected with at least one LED driving circuit in serial.