A high voltage open-drain electrostatic discharge (ESD) protection device is disclosed, which comprises a high-voltage n-channel metal oxide semiconductor field effect transistor (HV NMOSFET) coupled to a high-voltage pad and a low-voltage terminal and receiving a high voltage on the high-voltage pad to operate in normal operation. The high-voltage pad and the HV NMOSFET are further coupled to a high-voltage ESD unit blocking the high voltage, and receiving a positive ESD voltage on the high-voltage pad to bypass an ESD current when an ESD event is applied to the high-voltage pad. The high-voltage ESD unit and the low-voltage terminal are coupled to a power clamp unit, which receives the positive ESD voltage via the high-voltage ESD unit to bypass the ESD current.