A mutual awakening system and method thereof between a handheld device and a wireless communication module are disclosed. The system and method are applicable to the case that the wireless communication module is inserted and electrically coupled to the handheld device. The system includes a communication control line and a host control line which are used for electrically coupling the handheld device and the wireless communication module. When the handheld device is to transmit data, a second voltage signal of the communication control line is raised in value, which triggers a communication interrupt routine of the wireless communication module to awaken the wireless communication module from a sleep state. When the wireless communication module is to transmit data, a first voltage signal of the host control line is raised in value, which triggers a host interrupt routine of the handheld device to awaken the handheld device from a sleep state.