An electrostatic discharge protection device is provided. The electrostatic discharge protection device includes a clamp unit and a control circuit. The clamp unit provides a discharging path from a first power line to a first ground line. The control circuit receives a first power voltage from the first power line and a second power voltage from a second power line. Wherein, when the first power voltage and the second power voltage are applied, the control circuit generates an isolation signal to disconnect the discharging path. When the first power voltage and the second power voltage are not applied, the control circuit generates a trigger signal according to an electrostatic signal from the first power line to turn on the discharging path.