An ESD protection circuit with multiple domains, which comprises: an ESD protection device, coupled between a first power supplying line and a first ground line; a first internal circuit, having a first terminal coupled to the first power supplying line; a first switch, coupled between a second terminal of the first internal circuit and a second ground line; and a first ESD detection circuit, coupled to the first switch, for detecting an ESD signal, and controls the first switch to be non-conductive when the ESD signal occurs.